Aryl ether substituted imidazoquinolines

ABSTRACT

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain ether and aryl or alkenyl functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

[0001] This application is a continuation-in-part of Ser. No.10/013,202, filed on Dec. 6, 2001, which claims the benefit of SerialNo. 60/254,218, filed on Dec. 8, 2000.

FIELD OF THE INVENTION

[0002] This invention relates to imidazoquinoline compounds that have a1-substituent that contains ether and aryl or alkenyl functionality, andto pharmaceutical compositions containing such compounds. A furtheraspect of this invention relates to the use of these compounds asimmunomodulators, for inducing cytokine biosynthesis in animals, and inthe treatment of diseases, including viral and neoplastic diseases.

BACKGROUND OF THE INVENTION

[0003] The first reliable report on the 1H-imidazo[4,5-c]quinoline ringsystem, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes thesynthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c]quinolines were reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesizedthe compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as apossible anticonvulsant and cardiovascular agent. Also, Baranov et al.,Chem. Abs. 85, 94362 (1976), have reported several2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem.18, 1537-1540 (1981), have reported certain2-oxoimidazo[4,5-c]quinolines.

[0004] Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and2-substituted derivatives thereof were later found to be useful asantiviral agents, bronchodilators and immunomodulators. These aredescribed in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348;4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of whichare incorporated herein by reference.

[0005] There continues to be interest in the imidazoquinoline ringsystem. Certain 1H-imidazo[4,5-c]naphthyridine-4-amines,1H-imidazo[4,5-c]pyridin-4-amines, and1H-imidazo[4,5-c]quinolin-4-amines having an ether containingsubstituent at the 1 position are known. These are described in U.S.Pat. Nos. 5,268,376; 5,389,640; 5,494,916; and WO 99/29693.

[0006] There is a continuing need for compounds that have the ability tomodulate the immune response, by induction of cytokine biosynthesis orother mechanisms.

SUMMARY OF THE INVENTION

[0007] We have found a new class of compounds that are useful ininducing cytokine biosynthesis in animals. Accordingly, this inventionprovides imidazo[4,5-c]quinoline-4-amine andtetrahydroimidazo[4,5-c]quinoline-4-amine compounds that have an ethercontaining substituent at the 1-position. The compounds are described byFormulas (I), (II), (III) and (IV), which are defined in more detailinfra. These compounds share the general structural formula:

[0008] wherein X, R₁, R₂, and R are as defined herein for each class ofcompounds having Formulas (I), (II), (III) and (IV).

[0009] The compounds of Formulas (I), (II), (III), and (IV) are usefulas immune response modifiers due to their ability to induce cytokinebiosynthesis and otherwise modulate the immune response whenadministered to animals. This makes the compounds useful in thetreatment of a variety of conditions such as viral diseases and tumorsthat are responsive to such changes in the immune response.

[0010] The invention further provides pharmaceutical compositionscontaining the immune response modifying compounds, and methods ofinducing cytokine biosynthesis in an animal, treating a viral infectionin an animal, and/or treating a neoplastic disease in an animal byadministering a compound of Formula (I), (II), (III), or (IV) to theanimal.

[0011] In addition, the invention provides methods of synthesizing thecompounds of the invention and intermediates useful in the synthesis ofthese compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0012] As mentioned earlier, we have found certain compounds that inducecytokine biosynthesis and modify the immune response in animals. Suchcompounds are represented by Formulas (I), (II), (III), and (IV), asshown below.

[0013] Imidazoquinoline compounds of the invention, which have ether andaryl or alkenyl functionality at the 1-position are represented byFormula (I):

[0014] wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0015] R₁ is selected from the group consisting of:

[0016] -alkenyl;

[0017] -aryl;

[0018] —R₄-aryl;

[0019] R₂ is selected from the group consisting of:

[0020] -hydrogen;

[0021] -alkyl;

[0022] -alkenyl;

[0023] -aryl;

[0024] -heteroaryl;

[0025] -heterocyclyl;

[0026] -alkyl-Y-alkyl;

[0027] -alkyl-Y-alkenyl;

[0028] -alkyl-Y-aryl; and

[0029] alkyl or alkenyl substituted by one or more substituents selectedfrom the group consisting of:

[0030] —OH;

[0031] -halogen;

[0032] —N(R₃)₂;

[0033] —CO—N(R₃)₂;

[0034] —CO—C₁₋₁₀ alkyl;

[0035] —CO—O—C₁₋₁₀ alkyl;

[0036] —N₃;

[0037] -aryl;

[0038] -heteroaryl;

[0039] -heterocyclyl;

[0040] —CO-aryl; and

[0041] —CO-heteroaryl;

[0042] R₄ is alkyl or alkenyl, both of which may be interrupted by oneor more —O— groups;

[0043] each R₃ is independently H or C₁₋₁₀ alkyl;

[0044] each Y is independently —O— or —S(O)₀₋₂—;

[0045] n is 0 to 4; and

[0046] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0047] or a pharmaceutically acceptable salt thereof.

[0048] The invention also provides imidazoquinoline compounds thatcontain ether functionality at the 1-position, where the ethercontaining substituent also contains an alkynyl group. These compoundsare represented by structural Formula (II):

[0049] wherein X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0050] R₁₀ is selected from the group consisting of:

[0051] —H;

[0052] -alkyl;

[0053] -alkylaryl;

[0054] -alkenyl; and

[0055] -aryl;

[0056] R₂ is selected from the group consisting of:

[0057] -hydrogen;

[0058] -alkyl;

[0059] -alkenyl;

[0060] -aryl;

[0061] -heteroaryl;

[0062] -heterocyclyl;

[0063] -alkyl-Y-alkyl;

[0064] -alkyl-Y-alkenyl;

[0065] -alkyl-Y-aryl; and

[0066] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0067] —OH;

[0068] -halogen;

[0069] —N(R₃)₂;

[0070] —CO—N(R₃)₂;

[0071] —CO—C₁₋₁₀ alkyl;

[0072] —CO—O—C₁₋₁₀ alkyl;

[0073] —N₃;

[0074] -aryl;

[0075] -heteroaryl;

[0076] -heterocyclyl;

[0077] —CO-aryl; and

[0078] —CO-heteroaryl;

[0079] n is 0 to 4;

[0080] each Y is independently —O— or —S(O)₀₋₂—;

[0081] each R₃ is independently H or C₁₋₁₀ alkyl; and

[0082] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0083] or a pharmaceutically acceptable salt thereof.

[0084] The invention also includes tetrahydroimidazoquinoline compoundsthat bear an ether and aryl or alkenyl containing substituent at the1-position. Such tetrahydroimidazoquinoline compounds are represented byFormula (III):

[0085] wherein:

[0086] X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0087] R₁ is selected from the group consisting of:

[0088] aryl;

[0089] alkenyl; and

[0090] R₄-aryl;

[0091] R₂ is selected from the group consisting of:

[0092] -hydrogen;

[0093] -alkyl;

[0094] -alkenyl;

[0095] -aryl;

[0096] -heteroaryl;

[0097] -heterocyclyl;

[0098] -alkyl-Y-alkyl;

[0099] -alkyl-Y-aryl;

[0100] -alkyl-Y— alkenyl; and

[0101] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0102] —OH;

[0103] -halogen;

[0104] —N(R₃)₂;

[0105] —CO—N(R₃)₂;

[0106] —CO—C₁₋₁₀ alkyl;

[0107] —CO—O—C₁₋₁₀ alkyl;

[0108] —N₃;

[0109] -aryl;

[0110] -heteroaryl;

[0111] -heterocyclyl;

[0112] —CO-aryl; and

[0113] —CO-heteroaryl;

[0114] R₄ is alkyl or alkenyl, both of which may be interrupted by oneor more —O— groups;

[0115] each R₃ is independently H or C₁₋₁₀ alkyl;

[0116] each Y is independently —O— or —S(O)₀₋₂—;

[0117] n is 0 to 4; and

[0118] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0119] or a pharmaceutically acceptable salt thereof.

[0120] An additional class of immune response modifying compounds of theinvention are tetrahydroimidazoquinoline compounds that have an ethercontaining substituent at the 1-position, where the ether containingsubstituent also contains an alkynyl group. These compounds arerepresented by structural Formula (IV):

[0121] wherein

[0122] X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0123] R₁₀ is selected from the group consisting of:

[0124] —H;

[0125] -alkyl;

[0126] -alkylaryl;

[0127] -alkenyl; and

[0128] -aryl;

[0129] R₂ is selected from the group consisting of:

[0130] -hydrogen;

[0131] -alkyl;

[0132] -alkenyl;

[0133] -aryl;

[0134] -heteroaryl;

[0135] -heterocyclyl;

[0136] -alkyl-Y-alkyl;

[0137] -alkyl-Y-aryl;

[0138] -alkyl-Y-alkenyl; and

[0139] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0140] —OH;

[0141] -halogen;

[0142] —N(R₃)₂;

[0143] —CO—N(R₃)₂;

[0144] —CO—C₁₋₁₀ alkyl;

[0145] —CO—O—C₁₋₁₀ alkyl;

[0146] —N₃;

[0147] -aryl;

[0148] -heteroaryl;

[0149] -heterocyclyl;

[0150] —CO-aryl; and

[0151] —CO-heteroaryl;

[0152] each R₃ is independently H or C₁₋₁₀ alkyl;

[0153] each Y is independently —O— or —S(O)₀₋₂—;

[0154] n is 0 to 4; and

[0155] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0156] or a pharmaceutically acceptable salt thereof.

[0157] Preparation of the Compounds

[0158] Compounds of the invention can be prepared according to ReactionScheme I where R, R₂, X and n are as defined above and R₁₁ is alkylsubstituted by an aryl group wherein the aryl group may be unsubstitutedor may be substituted or R₁₁ is substituted aryl with the proviso thatif R₁₁ is substituted aryl at least one substituent is a strong electronwithdrawing group located ortho orpara to the ether bond.

Reaction Scheme I

[0159]

[0160] In Reaction Scheme I a 4-amino-1H-imidazo[4,5-c]quinolin-1-ylalcohol of Formula X is alkylated with a halide of Formula XI to providea 1H-imidazo[4,5-c]quinolin-4-amine of Formula XII which is a subgenusof Formula I. The alcohol of Formula X is reacted with sodium hydride ina suitable solvent such as N,N-dimethylformamide to form an alkoxide.The halide is then added to the reaction mixture. The reaction can becarried out at ambient temperature or with gentle heating (˜50° C.) ifdesired. The product or a pharmaceutically acceptable salt thereof canbe isolated using conventional methods.

[0161] Many compounds of Formula X are known, see for example Gerster,U.S. Pat. No. 4,689,338 and Gerster et. al., U.S. Pat. No. 5,605,899,the disclosures of which are incorporated by reference herein; otherscan readily be prepared using known synthetic routes, see for example,Andre et. al, U.S. Pat. No. 5,578,727; Gerster, U.S. Pat. No. 5,175,296;Nikolaides et al., U.S. Pat. No. 5,395,937; and Gerster et. al., U.S.Pat. No. 5,741,908, the disclosures of which are incorporated byreference herein. Many halides of Formula XI are commercially available;others can be readily prepared using known synthetic methods.

[0162] Compounds of the invention can be prepared according to ReactionScheme II where R, R₂, R₁₁, X and n are as defined above.

[0163] In step (1) of Reaction Scheme II a1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XIII is alkylated witha halide of Formula XI to provide a 1H-imidazo[4,5-c]quinolin-1-yl etherof Formula XIV. The alcohol of Formula XIII is reacted with sodiumhydride in a suitable solvent such as N,N-dimethylformamide ortetrahydrofuran to form an alkoxide. The alkoxide is then combined withthe halide Alternatively, the alcohol and the halide can be combined ina biphasic mixture of aqueous 50% sodium hydroxide and an inert solventsuch as dichloromethane in the presence of a phase transfer catalystsuch as benzyltrimethylammonium chloride. The reaction can be carriedout at ambient temperature. Many compounds of Formula XIII are known,see for example, Gerster, U.S. Pat. No. 4,689,338; others can readily beprepared using known synthetic routes, see for example, Gerster et al.,U.S. Pat. No. 5,605,899 and Gerster, U.S. Pat. No. 5,175,296.

[0164] In step (2) of Reaction Scheme II a1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XIV is oxidized toprovide a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XV using aconventional oxidizing agent capable of forming N-oxides. Preferably asolution of a compound of Formula XIV in a suitable solvent such aschloroform or dichloromethane is oxidized using 3-chloroperoxybenzoicacid at ambient temperature.

[0165] In step (3) of Reaction Scheme II a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XV is aminated to providea 1H-imidazo[4,5-c]quinolin-4-amine of Formula XII which is a subgenusof Formula I. Step (3) involves (i) reacting a compound of Formula XVwith an acylating agent and then (ii) reacting the product with anaminating agent. Part (i) of step (3) involves reacting an N-oxide ofFormula XV with an acylating agent. Suitable acylating agents includealkyl- or arylsulfonyl chlorides (e.g., benezenesulfonyl chloride,methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonylchlorides are preferred. Para-toluenesulfonyl chloride is mostpreferred. Part (ii) of step (3) involves reacting the product of part(i) with an excess of an aminating agent. Suitable aminating agentsinclude ammonia (e.g., in the form of ammonium hydroxide) and ammoniumsalts (e.g., ammonium carbonate, ammonium bicarbonate, ammoniumphosphate). Ammonium hydroxide is preferred. The reaction is preferablycarried out by dissolving the N-oxide of Formula XV in an inert solventsuch as dichloromethane, adding the aminating agent to the solution, andthen slowly adding the acylating agent. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0166] Alternatively, step (3) may be carried out by (i) reacting anN-oxide of Formula XV with an isocyanate and then (ii) hydrolyzing theresulting product. Part (i) involves reacting the N-oxide with anisocyanate wherein the isocyanato group is bonded to a carbonyl group.Preferred isocyanates include trichloroacetyl isocyanate and aroylisocyanates such as benzoyl isocyanate. The reaction of the isocyanatewith the N-oxide is carried out under substantially anhydrous conditionsby adding the isocyanate to a solution of the N-oxide in an inertsolvent such as chloroform or dichloromethane. Part (ii) involveshydrolysis of the product from part (i). The hydrolysis can be carriedout by conventional methods such as heating in the presence of water ora lower alkanol optionally in the presence of a catalyst such as analkali metal hydroxide or lower alkoxide. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0167] Compounds of Formula I wherein R, R₂, X and n are as definedabove and R₁ is an optionally substituted phenyl can be preparedaccording to Reaction Scheme III where m is 0 to 3 and each R′ isindependently selected from the group consisting of alkyl, alkoxy,alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro,mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy,arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio,heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino,heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl,arylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,alkylthiocarbonyl, aryloxycarbonyl, alkanoyloxy, alkanoylthio,alkanoylamino, aroyloxy and aroylamino.

[0168] In Reaction Scheme III a 4-amino-1H-imidazo[4,5-c]quinolin-1-ylalcohol of Formula X is condensed with a phenol of Formula XVI toprovide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII which is asubgenus of Formula I. Preferably, a solution of a compound of Formula Xand the phenol in a suitable solvent such as N,N-dimethylformamide istreated with diethyl azodicarboxylate and triphenylphosphine at ambienttemperature. The product or a pharmaceutically acceptable salt thereofcan be isolated using conventional methods.

[0169] Compounds of the invention can also be prepared according toReaction Scheme IV where R, R₂, R₁₁, X and n are as defined above.

[0170] In step (1) of Reaction Scheme IV the hydroxy group of a1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XIII is protected witha benzyl group. The alcohol of Formula XIII is reacted with sodiumhydride in a suitable solvent such as N,N-dimethylformamide to form analkoxide. The alkoxide is then alkylated with benzyl bromide to providea compound of Formula XVIII. The reaction can be carried out at ambienttemperature.

[0171] In step (2) of Reaction Scheme IV a compound of Formula XVIII isoxidized using the method of step (2) of Reaction Scheme II to provide a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XIX.

[0172] In step (3) of Reaction Scheme IV a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XIX is chlorinated toprovide a 4-chloro-1H-imidazo[4,5-c]quinoline of Formula XX. Preferablya solution of a compound of Formula XIX in a suitable solvent such astoluene is treated with phosphorous oxychloride at ambient temperature.

[0173] In step (4) of Reaction Scheme IV a4-chloro-1H-imidazo[4,5-c]quinoline of Formula XX is reacted with phenolto provide a 4-phenoxy-1H-imidazo[4,5-c]quinoline of Formula XXI. Thephenol is reacted with sodium hydride in a suitable solvent such asdiglyme to form a phenoxide. The phenoxide is then reacted at anelevated temperature with a compound of Formula XX.

[0174] In step (5) of Reaction Scheme IV the benzyl protecting group isremoved from a compound of Formula XXI to provide a4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XXII. Thereaction is preferably carried out by adding triflic acid in acontrolled fashion to a solution of a compound of Formula XXI in asuitable solvent such as dichloromethane at ambient temperature.

[0175] In step (6) of Reaction Scheme IV a4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XXII isalkylated with a halide of Hal-R₁₁ to provide a4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XXIII. Thealkoxide of a compound of Formula XXII is formed by adding the alcoholto a biphasic mixture of aqueous 50% sodium hydroxide and an inertsolvent such as dichloromethane in the presence of a phase transfercatalyst such as benzyltrimethlammonium chloride. The alkoxide is thenalkylated. The reaction can be carried out at ambient temperature.

[0176] In step (7) of Reaction Scheme IV a4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XXIII isaminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XIIwhich is a subgenus of Formula I. The reaction can be carried out bycombining a compound of Formula XXIII with ammonium acetate and heatingthe resulting mixture at ˜150° C. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

[0177] Tetrahydroimidazoquinolines of the invention can be preparedaccording to Reaction Scheme V where R, R₂, R₁ ₁, X and n are as definedabove.

[0178] In Reaction Scheme V a4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl alcohol ofFormula XXIV is alkylated with a halide of Formula XI to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XXVwhich is a subgenus of Formula III. The alcohol of Formula XXIV isreacted with sodium hydride in a suitable solvent such asN,N-dimethylformamide to form an alkoxide. The alkoxide is then combinedwith the halide. The reaction can be carried out at ambient temperature.The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

[0179] Many tetrahydro-1H-imidazo[4,5-c]quinolines of Formula XXIV areknown, see for example, Nikolaides et al., U.S. Pat. No. 5,352,784;others can be prepared using known synthetic methods, see for example,Lindstrom, U.S. Pat. No. 5,693,811; the disclosures of which areincorporated by reference herein.

[0180] Compounds of the invention can also be prepared according toReaction Scheme VI where R, R₁, R₂, X and n are as defined above.

[0181] In step (1) of Reaction Scheme VI a 4-chloro-3-nitroquinoline ofFormula XXVI is reacted with an amine of Formula R₁—O—X—NH₂ to provide a3-nitroquinolin-4-amine of Formula XXVII. The reaction can be carriedout by adding the amine to a solution of a compound of Formula XXVI in asuitable solvent such as chloroform or dichloromethane and optionallyheating. Many quinolines of Formula XXVI are known compounds (see forexample, U.S. Pat. No. 4,689,338 and references cited therein).

[0182] In step (2) of Reaction Scheme VI a 3-nitroquinolin-4-amine ofFormula XXVII is reduced to provide a quinoline-3,4-diamine of FormulaXXVIII. Preferably, the reduction is carried out using a conventionalheterogeneous hydrogenation catalyst such as platinum on carbon orpalladium on carbon. The reaction can conveniently be carried out on aParr apparatus in a suitable solvent such as isopropyl alcohol orpreferably toluene.

[0183] In step (3) of Reaction Scheme VI a quinoline-3,4-diamine ofFormula XXVIII is reacted with a carboxylic acid or an equivalentthereof to provide a 1H-imidazo[4,5-c]quinoline of Formula XXIX.Suitable equivalents to carboxylic acid include orthoesters, and1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent isselected such that it will provide the desired R₂ substituent in acompound of Formula XXIX. For example, triethyl orthoformate willprovide a compound where R₂ is hydrogen and triethyl orthoacetate willprovide a compound where R₂ is methyl. The reaction can be run in theabsence of solvent or in an inert solvent such as toluene. The reactionis run with sufficient heating to drive off any alcohol or water formedas a byproduct of the reaction. Optionally a catalyst such as pyridinehydrochloride can be included.

[0184] Alternatively, step (3) can be carried out by (i) reacting thediamine of Formula XXVIII with an acyl halide of Formula R₂C(O)Cl andthen (ii) cyclizing. In part (i) the acyl halide is added to a solutionof the diamine in a suitable solvent such as acetonitrile, pyridine ordichloromethane. The reaction can be carried out at ambient temperature.In part (ii) the product of part (i) is heated in an alcoholic solventin the presence of a base. Preferably the product of part (i) isrefluxed in ethanol in the presence of an excess of triethylamine orheated with methanolic ammonia. Alternatively, if step (i) has been runin pyridine, step (ii) can be carried out by heating the reactionmixture after analysis indicates that step (i) is complete.

[0185] In step (4) of Reaction Scheme VI a 1H-imidazo[4,5-c]quinoline ofFormula XXIX is oxidized using the method of step (2) of Reaction SchemeII to provide a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XXX Instep (5) of Reaction Scheme VI a 1H-imidazo[4,5-c]quinoline-5N-oxide ofFormula XXX is aminated using the method of step (3) of Reaction SchemeII to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula I.

[0186] Compounds of the invention can be prepared according to ReactionScheme VII where R, R₂, X and n are as defined above and R₁₂ is an arylgroup which may be unsubstituted or substituted as defined above.

[0187] In step (1) of Reaction Scheme VII a1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XIII is alkylated witha halide of Formula XXXI to provide a 1H-imidazo[4,5-c]quinolin-1-ylether of Formula XXXII. The compound of Formula XIII and the halide ofFormula XXXI are combined in a biphasic mixture of 50% aqueous sodiumhydroxide and a suitable solvent such as dichloromethane in the presenceof a phase transfer catalyst such as benzyltrimethylammonium chloride.The reaction can be run at ambient temperature.

[0188] In step (2) of Reaction Scheme VII a 1H-imidazo[4,5-c]quinolineof Formula XXXII is oxidized using the method of step (2) of ReactionScheme II to provide a 1H-imidazo[4,5-c]quinoline-5N-oxide of FormulaXXXIII.

[0189] In step (3) of Reaction Scheme VII a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XXXIII is reacted withtrichloroacetyl isocyanate to provide a 1H-imidazo[4,5-c]quinolin-4-yltrichloroacetamide of Formula XXXIV. Preferably the isocyanate is addedin a controlled fashion at ambient temperature to a solution of the5N-oxide in a suitable solvent such as dichloromethane.

[0190] In step (4) of Reaction Scheme VII a1H-imidazo[4,5-c]quinolin-4-yl trichloroacetamide of Formula XXXIV ishydrolyzed to provide a 1H-imidazo[4,5-c]quinolin-4-amine of FormulaXXXV which is a subgenus of Formula II. The hydrolysis can be carriedout by conventional methods, preferably by treating a solution of acompound of Formula XXXIV in methanol with sodium methoxide.

[0191] In step (5) of Reaction Scheme VII1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXV is coupled with ahalide of formula Hal-R₁₂ using a transition metal catalyst to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXVI which is a subgenusof Formula II. Preferably a compound of Formula XXXV is combined withthe halide in the presence of copper (I) iodide,dichlorobis(triphenylphosphine)palladium(II), and excess triethylaminein a suitable solvent such as N,N-dimethylformamide or acetonitrile. Thereaction is preferably carried out at an elevated temperature (60-80°C.). The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

[0192] Compounds of the invention can be prepared according to ReactionScheme VIII where R, R₂, R₁₂, X and n are as defined above and BOC istert-butoxycarbonyl.

[0193] In step (1) of Reaction Scheme VIII the amino group of a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXV is protected with twotert-butoxycarbonyl groups. A compound of Formula XXXV is combined withdi-tert-butyl dicarbonate in a suitable solvent such asN,N-dimethylformamide in the presence of 4-(dimethylamino)pyridine andtriethylamine. The reaction is carried out at an elevated temperature(80-85° C.).

[0194] In step (2) of Reaction Scheme VIII a protected1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXVII is coupled with ahalide of formula Hal-R₁₂ using a transition metal catalyst to provide aprotected 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXVIII.Preferably a compound of Formula XXXVII is combined with the halide inthe presence of copper (I) iodide,dichlorobis(triphenylphosphine)palladium(II), and excess triethylaminein a suitable solvent such as N,N-dimethylformamide or acetonitrile. Thereaction can be carried out at ambient temperature or at an elevatedtemperature (40-80° C.).

[0195] In step (3) of Reaction Scheme VIII the protecting groups areremoved by hydrolysis under acidic conditions to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXVI which is a subgenusof Formula II. Preferably a compound of Formula XXXVIII is treated withtrifluoroacetic acid in a suitable solvent such as dichloromethane. Thereaction can be run at ambient temperature or at a reduced temperature(0° C.). The product or a pharmaceutically acceptable salt thereof canbe isolated using conventional methods.

[0196] In step (4) of Reaction Scheme VIII the alkyne bond of aprotected 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXVIII isreduced to provide a protected 1H-imidazo[4,5-c]quinolin-4-amine ofFormula XXXIX. Preferably, the reduction is carried out using aconventional heterogeneous hydrogentation catalyst such as platinumoxide, platinum on carbon or palladium on carbon. The reaction canconveniently be carried out on a Parr apparatus in a suitable solventsuch as methanol.

[0197] In step (5) of Reaction Scheme VIII the protecting groups of acompound of Formula XXXIX are removed in the same manner as in step (3)to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XL which is asubgenus of Formula I. The product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

[0198] Compounds of the invention can be prepared according to ReactionScheme IX where R, R₂, R₁₂, X and n are as defined above and CBZ isbenzyloxycarbonyl.

[0199] In step (1) of Reaction Scheme 1× the amino group of a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXV is protected withbenzyloxycarbonyl groups. A compound of Formula XXXV is combined withdibenzyl dicarbonate in a suitable solvent such asN,N-dimethylformamide. The reaction can be carried out at ambienttemperature or with mild heating (40° C.).

[0200] In step (2) of Reaction Scheme IX a protected1H-imidazo[4,5-c]quinolin-4-amine of Formula XLI is coupled with ahalide of formula Hal-R₁₂ using a transition metal catalyst to provide aprotected 1H-imidazo[4,5-c]quinolin-4-amine of Formula XLII. Preferablya compound of Formula XLI is combined with the halide in the presence ofcopper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), andexcess triethylamine in a suitable solvent such as N,N-dimethylformamideor acetonitrile. The reaction can be carried out at ambient temperatureor at an elevated temperature (40-80° C.).

[0201] In step (3) of Reaction Scheme IX the protecting groups areremoved by hydrolysis to provide a 1H-imidazo[4,5-c]quinolin-4-amine ofFormula XXXVI which is a subgenus of Formula II. Preferably a compoundof Formula XLII is treated with sodium methoxide in a suitable solventsuch as methanol. The reaction can be run at ambient temperature. Theproduct or a pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

[0202] In step (4) of Reaction Scheme 1× the protecting groups of acompound of Formula XLII are removed by hydrogenolysis and the alkynebond is reduced to provide a 1H-imidazo[4,5-c]quinolin-4-amine ofFormula XL which is a subgenus of Formula I. Preferably, thehydrogenolysis/reduction is carried out using palladium hydroxide oncarbon. The reaction can conveniently be carried out on a Parr apparatusin a suitable solvent such as methanol. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0203] Compounds of the invention can be prepared according to ReactionScheme X where R, R₁, R₂, X and n are as defined above.

[0204] In step (1) of Reaction Scheme X a 2,4-dichloro-3-nitroquinolineof Formula XLIII is reacted with an amine of Formula R₁—O—X—NH₂ toprovide a 2-chloro-3-nitroquinolin-4-amine of Formula XLIV. The reactioncan be carried out by adding the amine to a solution of a compound ofFormula XLIII in a suitable solvent such as chloroform ordichloromethane and optionally heating. Many quinolines of Formula XLIIIare known or can be prepared using known synthetic methods (see forexample, Andre et al., U.S. Pat. No. 4,988,815 and references citedtherein).

[0205] In step (2) of Reaction Scheme X a2-chloro-3-nitroquinolin-4-amine of Formula XLIV is reduced using themethod of step (2) in Reaction Scheme VI to provide a2-chloroquinoline-3,4-diamine of Formula XLV.

[0206] In step (3) of Reaction Scheme X a 2-chloroquinoline-3,4-diamineof Formula XLV is cyclized using the method of step (3) in ReactionScheme VI to provide a 4-chloro-1H-imidazo[4,5-c]quinoline of FormulaXLVI.

[0207] In step (4) of Reaction Scheme X a4-chloro-1H-imidazo[4,5-c]quinoline of Formula XLVI is aminated toprovide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula I. The reactionis carried out by heating (e.g., 125-175° C.) a compound of Formula XLVIunder pressure in a sealed reactor in the presence of a solution ofammonia in an alkanol.

[0208] The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

[0209] Compounds of the invention can be prepared according to ReactionScheme XI where R, R₁, R₂, X and n are as defined above.

[0210] In Reaction Scheme XI a 1H-imidazo[4,5-c]quinolin-4-amine ofFormula XLVII is alkylated with a halide of Formula XLVIII to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula I. The compound of FormulaXLVII is reacted with sodium hydride in a suitable solvent such asN,N-dimethylformamide. The halide is then added to the reaction mixture.The reaction can be carried out at an elevated temperature (˜100° C.).Alkylation occurs at both the N1 and the N3 nitrogens; however, thedesired 1-isomer can be readily separated from the 3-isomer usingconventional techniques such as column chromatography andrecrystallization.

[0211] Many 1H-imidazo[4,5-c]quinolin-4-amines of Formula XLVII areknown; others may be prepared using known synthetic methods, see forexample, Gerster, U.S. Pat. No. 5,756,747 and the references citedtherein.

[0212] Compounds of the invention can be prepared according to ReactionScheme XII where R, R₁ R₂, X and n are as defined above.

[0213] In step (1) of Reaction Scheme XII a4-nitrotetrazolo[1,5-a]quinolin-5-ol of Formula XLIX is chlorinated toprovide a 5-chloro-4-nitrotetrazolo[1,5-a]quinoline of Formula L.Conventional chlorinating agents can be used. Preferably the reaction iscarried out using phosphorus oxychloride in a suitable solvent such asN,N-dimethylformamide. 4-Nitrotetrazolo[1,5-a]quinolin-5-ols of FormulaXLIX are known or can be prepared using known synthetic methods (see forexample, Gerster, et al., U.S. Pat. No. 5,741,908 and references citedtherein).

[0214] In step (2) of Reaction Scheme XII a5-chloro-4-nitrotetrazolo[1,5-a]quinoline of Formula L is reacted withan amine of Formula R₁—O—X—NH₂ to provide a4-nitrotetrazolo[1,5-a]quinolin-5-amine of Formula LI. The reaction canbe carried out by adding the amine to a solution of a compound ofFormula L in a suitable solvent such as dichloromethane in the presenceof triethylamine.

[0215] In step (3) of Reaction Scheme XII a4-nitrotetrazolo[1,5-a]quinolin-5-amine of Formula LI is reduced usingthe method of step (2) in Reaction Scheme VI to provide atetrazolo[1,5-a]quinolin-4,5-diamine of Formula LII.

[0216] In step (4) of Reaction Scheme XII atetrazolo[1,5-a]quinolin-4,5-diamine of Formula LII is cyclized usingthe method of step (3) in Reaction Scheme VI to provide a6H-imidazo[4,5-c]tetrazolo[1,5-α]quinoline of Formula LIII.

[0217] In step (5) of Reaction Scheme XII a6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline of Formula LIII is reduced toprovide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula I. Step (5)involves (i) reacting a compound of Formula LIII with triphenylphosphineand then (ii) hydrolyzing. Part (i) can be carried out by combining acompound of Formula LIII with triphenylphosphine in a suitable solventsuch as 1,2-dichlorobenzene and heating. Part (ii) involves hydrolysisof the product from part (i). The hydrolysis can be carried out byconventional methods such as heating in the presence of water or a loweralkanol optionally in the presence of a catalyst such as an alkali metalhydroxide or lower alkoxide. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

[0218] Compounds of the invention can be prepared according to ReactionScheme XIII where R, R₂, R₁₂, X and n are as defined above.

[0219] In step (1) of Reaction Scheme XIII a1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XXXII is coupled with ahalide of Formula Hal-R₁₂ using the method of step (5) in ReactionScheme VII to provide a 1H-imidazo[4,5-c]quinolin-1-yl ether of FormulaLIV.

[0220] In step (2) of Reaction Scheme XIII a1H-imidazo[4,5-c]quinolin-1-yl ether of Formula LIV is oxidized usingthe method of step (2) in Reaction Scheme II to provide a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula LV.

[0221] In step (3) of Reaction Scheme XIII a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula LV is aminated using themethod of step (3) in Reaction Scheme II to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXVI which is a subgenusof Formula II. The product or a pharmaceutically acceptable salt thereofcan be isolated using conventional methods.

[0222] Compounds of the invention can be prepared according to ReactionScheme XIV where R, R₂, R₁₂, X and n are as defined above.

[0223] In step (1) of Reaction Scheme XIV the alkyne bond of a1H-imidazo[4,5-c]quinolin-1-yl ether of Formula LIV is reduced using themethod of step (4) of Reaction Scheme VIII to provide a1H-imidazo[4,5-c]quinolin-1-yl ether of Formula LVI.

[0224] In step (2) of Reaction Scheme XIV a1H-imidazo[4,5-c]quinolin-1-yl ether of Formula LVI is oxidized usingthe method of step (2) in Reaction Scheme II to provide a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula LVII.

[0225] In step (3) of Reaction Scheme XIV a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula LVII is aminated usingthe method of step (3) in Reaction Scheme II to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula XL which is a subgenus ofFormula I. The product or a pharmaceutically acceptable salt thereof canbe isolated using conventional methods.

[0226] Tetrahydroimidazoquinolines of the invention can be preparedaccording to Reaction Scheme XV where R, R₂, R₁₂, X and n are as definedabove.

[0227] In step (1) of Reaction Scheme XV a4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl alcohol ofFormula XXIV is alkylated using the method described in Reaction SchemeV with a halide of Formula Hal-(CH₂)₁₋₁₀—CH≡H to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula LVIIIwhich is a subgenus of Formula IV.

[0228] In step (2) of Reaction Scheme XV a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula LVIII iscoupled using the method of step (5) of Reaction Scheme VII with ahalide of Formula Hal-R₁₂ to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula LIXwhich is a subgenus of Formula IV. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

[0229] Compounds of the invention can be prepared according to ReactionScheme XVI where R, R₁, R₂, X and n are as defined above.

[0230] In step (1) of Reaction Scheme XVI a2,4-dihydroxy-3-nitro-6,7,8,9-tetrayhydroquinoline of Formula LX ischlorinated to provide a2,4-dichloro-3-nitro-6,7,8,9-tetrayhydroquinoline of Formula LXI.Conventional chlorinating agents can be used. Preferably the reaction iscarried out by combining a compound of Formula LX with phosphorousoxychloride and then heating (55-65° C.). Compounds of Formula LX areknown or can be prepared using known synthetic methods (see for exampleNikolaides et al,. U.S. Pat. No. 5,352,784 and references citedtherein).

[0231] In step (2) of Reaction Scheme XVI a2,4-dichloro-3-nitro-6,7,8,9-tetrayhydroquinoline of Formula LXI isreacted with an amine of Formula R₁—O—X—NH₂ to provide a2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula LXII. Thereaction can be carried out by adding the amine to a solution of acompound of Formula LXI in a suitable solvent such asN,N-dimethylformamide and heating (55-65° C.).

[0232] In step (3) of Reaction Scheme XVI a2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula LXII isreacted with phenol using the method of step (4) of Reaction Scheme IVto provide a 2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine ofFormula LXIII.

[0233] In step (4) of Reaction Scheme XVI a2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula LXIII isreduced using the method of step (2) of Reaction Scheme VI to provide a2-phenoxy-6,7,8,9-tetrahydroquinolin-3,4-diamine of Formula LXIV.

[0234] In step (5) of Reaction Scheme XVI a2-phenoxy-6,7,8,9-tetrahydroquinolin-3,4-diamine of Formula LXIV iscyclized using the method of step (3) of Reaction Scheme VI to provide a4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula LXV.

[0235] In step (6) of Reaction Scheme XVI a4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula LXVis aminated using the method of step (7) of Reaction Scheme IV toprovide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine ofFormula III.

[0236] Compounds of the invention can also be prepared by combiningsteps from two or more of the above Reaction Schemes I-XVI. For Example,compounds of the Formula XXXVI (in Reaction Scheme VIII) can be preparedfrom compounds of the Formula X (in Reaction Scheme III) by combiningthe method of step (1) of Reaction Scheme VII with the methods of steps(1)-(3) of Reaction Scheme XIII. In another example, compounds of theFormula XL (in Reaction Scheme VIII) can be prepared from compounds ofthe Formula XXXVI using the method of step (4) in Reaction Scheme VIII.

[0237] The invention also provides novel compounds useful asintermediates in the synthesis of the compounds of Formulas (I), (II),(III), and (IV). These intermediate compounds have the structuralFormulas (V)-(IX), described in more detail below.

[0238] One class of intermediate compounds has Formula (V):

[0239] wherein X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0240] R₁ is selected from the group consisting of:

[0241] -aryl;

[0242] -alkenyl;

[0243] —R₄-aryl; and

[0244] —(CH₂)₁₋₁₀—C≡C—R₁₀;

[0245] R₂ is selected from the group consisting of:

[0246] -hydrogen;

[0247] -alkyl;

[0248] -alkenyl;

[0249] -aryl;

[0250] -heteroaryl;

[0251] -heterocyclyl;

[0252] -alkyl-Y-alkyl;

[0253] -alkyl-Y-alkenyl;

[0254] -alkyl-Y-aryl; and

[0255] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0256] —OH;

[0257] -halogen;

[0258] —N(R₃)₂;

[0259] —CO—N(R₃)₂;

[0260] —CO—C₁₋₁₀ alkyl;

[0261] —CO—O—C₁₋₁₀ alkyl;

[0262] —N₃;

[0263] -aryl;

[0264] -heteroaryl;

[0265] -heterocyclyl;

[0266] —CO-aryl; and

[0267] —CO-heteroaryl;

[0268] R₄ is alkyl or alkenyl, which may be interrupted by one or more—O— groups;

[0269] each R₃ is independently H or C₁₋₁₀ alkyl;

[0270] R₁₀ is selected from the group consisting of H, alkyl, alkenyl,aryl, and -alkylaryl;

[0271] each Y is independently —O— or —S(O)₀₋₂—;

[0272] n is 0 to 4; and

[0273] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0274] or a pharmaceutically acceptable salt thereof.

[0275] Another class of intermediates are imidazoquinoline-4-phenoxycompounds of Formula (VI):

[0276] wherein X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0277] R₁ is selected from the group consisting of:

[0278] -aryl;

[0279] -alkenyl;

[0280] —R₄-aryl; and

[0281] —(CH₂)₁₋₁₀—C≡C—R₁₀;

[0282] R₂ is selected from the group consisting of:

[0283] -hydrogen;

[0284] -alkyl;

[0285] -alkenyl;

[0286] -aryl;

[0287] -heteroaryl;

[0288] -heterocyclyl;

[0289] -alkyl-Y-alkyl;

[0290] alkyl-Y-alkenyl;

[0291] alkyl-Y-aryl; and

[0292] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0293] —OH;

[0294] -halogen;

[0295] —N(R₃)₂;

[0296] —CO—N(R₃)₂;

[0297] —CO—C₁₋₁₀ alkyl;

[0298] —CO—O—C₁₋₁₀ alkyl;

[0299] —N₃;

[0300] -aryl;

[0301] -heteroaryl;

[0302] -heterocyclyl;

[0303] —CO-aryl; and

[0304] —CO-heteroaryl;

[0305] R₄ is alkyl or alkenyl, both of which may be interrupted by oneor more —O— groups;

[0306] each R₃ is independently H or C₁₋₁₀ alkyl;

[0307] R₁₀ is selected from the group consisting of H, alkyl, alkenyl,aryl, and -alkylaryl;

[0308] each Y is independently —O— or —S(O)₀₋₂—;

[0309] n is 0 to 4; and

[0310] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0311] or a pharmaceutically acceptable salt thereof.

[0312] Another class of intermediate compounds are theimidazoquinoline-N-oxide compounds of Formula (VII):

[0313] wherein X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0314] R₁ is selected from the group consisting of:

[0315] -aryl;

[0316] -alkenyl;

[0317] —R₄-aryl; and

[0318] —(CH₂)₁₋₁₀—C≡C—R₁₀;

[0319] R₄ is alkyl or alkenyl, both of which may be interrupted by oneor more —O— groups;

[0320] each R₃ is independently H or C₁₋₁₀ alkyl;

[0321] R₁₀ is selected from the group consisting of H, alkyl, alkenyl,aryl, and -alkylaryl;

[0322] n is 0 to 4; and

[0323] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0324] or a pharmaceutically acceptable salt thereof.

[0325] An additional class of intermediate compounds has the Formula(VIII):

[0326] wherein X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0327] R₁ is selected from the group consisting of:

[0328] -aryl;

[0329] -alkenyl;

[0330] —R₄-aryl; and

[0331] —(CH₂)₁₋₁₀—C≡C—R₁₀;

[0332] R₂ is selected from the group consisting of:

[0333] -hydrogen;

[0334] -alkyl;

[0335] -alkenyl;

[0336] -aryl;

[0337] -heteroaryl;

[0338] -heterocyclyl;

[0339] -alkyl-Y-alkyl;

[0340] -alkyl-Y-alkenyl;

[0341] -alkyl-Y-aryl; and

[0342] alkyl or alkenyl substituted by one or more substituents selectedfrom the group consisting of:

[0343] —OH;

[0344] -halogen;

[0345] —N(R₃)₂;

[0346] —CO—N(R₃)₂;

[0347] —CO—C₁₋₁₀ alkyl;

[0348] —CO—O—C₁₋₁₀ alkyl;

[0349] —N₃;

[0350] -aryl;

[0351] -heteroaryl;

[0352] -heterocyclyl;

[0353] —CO-aryl; and

[0354] —CO-heteroaryl;

[0355] R₄ is alkyl or alkenyl, which may be interrupted by one or more—O— groups;

[0356] each R₃ is independently H or C₁₋₁₀ alkyl;

[0357] R₁₀ is selected from the group consisting of H, alkyl, alkenyl,aryl, and -alkylaryl;

[0358] each Y is independently —O— or —S(O)₀₋₂—;

[0359] n is 0 to 4;

[0360] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl; and

[0361] R₇ is tert-butyl or benzyl;

[0362] or a pharmaceutically acceptable salt thereof.

[0363] A further class of intermediates are imidazoquinoline-4-chlorocompounds of the Formula (IX)

[0364] wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-;

[0365] R₁ is selected from the group consisting of:

[0366] aryl;

[0367] alkenyl;

[0368] R₄-aryl; and

[0369] —(CH₂)₁₋₁₀—C≡H

[0370] R₂ is selected from the group consisting of:

[0371] -hydrogen;

[0372] -alkyl;

[0373] -alkenyl;

[0374] -aryl;

[0375] -heteroaryl;

[0376] -heterocyclyl;

[0377] -alkyl-Y-alkyl;

[0378] -alkyl-Y-alkenyl;

[0379] -alkyl-Y-aryl; and

[0380] -alkyl or alkenyl substituted by one or more substituentsselected from the group consisting of:

[0381] —OH;

[0382] -halogen;

[0383] —N(R₃)₂;

[0384] —CO—N(R₃)₂;

[0385] —CO—C₁₋₁₀ alkyl;

[0386] —CO—O—C₁₋₁₀ alkyl;

[0387] —N₃;

[0388] -aryl;

[0389] -heteroaryl;

[0390] -heterocyclyl;

[0391] —CO-aryl; and

[0392] —CO-heteroaryl;

[0393] R₄ is alkyl or alkenyl, which may be interrupted by one or more—O— groups;

[0394] each R₃ is independently H or C₁₋₁₀ alkyl;

[0395] each Y is independently —O— or —S(O)₀₋₂—;

[0396] n is 0 to 4; and

[0397] each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl;

[0398] or a pharmaceutically acceptable salt thereof.

[0399] As used herein, the terms “alkyl”, “alkenyl” and the prefix“alk-” are inclusive of both straight chain and branched chain groupsand of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwisespecified, these groups contain from 1 to 20 carbon atoms, with alkenylgroups containing from 2 to 20 carbon atoms. Preferred groups have atotal of up to 10 carbon atoms. Where “alkyl” and “alkenyl” are shownwith two bonds, i.e. -alkyl- and -alkenyl-, they are understood to bealkylene and alkenylene groups, respectively. Cyclic groups can bemonocyclic or polycyclic and preferably have from 3 to 10 ring carbonatoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, and adamantyl.

[0400] In addition, the alkyl and alkenyl portions of —X— groups can beunsubstituted or substituted by one or more substituents, whichsubstituents are selected from the group consisting of alkyl, alkenyl,aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, andheterocyclylalkyl.

[0401] The term “haloalkyl” is inclusive of groups that are substitutedby one or more halogen atoms, including perfluorinated groups. This isalso true of groups that include the prefix “halo-”. Examples ofsuitable haloalkyl groups are chloromethyl, trifluoromethyl, and thelike.

[0402] The term “aryl” as used herein includes carbocyclic aromaticrings or ring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromaticrings or ring systems that contain at least one ring hetero atom (e.g.,O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl,quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl,tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl,benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl,quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl,purinyl, quinazolinyl, and so on.

[0403] “Heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring hetero atom (e.g., O, S, N) and includes allof the fully saturated and partially unsaturated derivatives of any ofthe above mentioned heteroaryl groups. Exemplary heterocyclic groupsinclude pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl,isothiazolidinyl, and the like.

[0404] The aryl, heteroaryl, and heterocyclyl groups can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, alkylthio,haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, nitrilo, hydroxy,mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy,arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio,heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino,heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl,alkanoyloxy, alkanoylthio, alkanoylamino, aroyloxy, aroylthio,aroylamino, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, alkylcarbonylamino, alkenylcarbonylamino,arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino,heteroarylalkylcarbonylamino, alkylsulfonylamino, alkenylsulfonylamino,arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino,heteroarylalkylsulfonylamino, alkylaminocarbonylamino,alkenylaminocarbonylamino, arylaminocarbonylamino,arylalkylaminocarbonylamino, heteroarylaminocarbonylamino,heteroarylalkylaminocarbonylamino, and, in the case of heterocyclyl,oxo. If any other groups are identified as being “substituted” or“optionally substituted”, then those groups can also be substituted byone or more of the above enumerated substituents.

[0405] Certain substituents are generally preferred. For example,R₄-aryl is a preferred R₁ group and preferred R₁₀ groups are alkyl andaryl, with phenyl or substituted phenyl being a preferred aryl group.Preferably no R substituents are present (i.e., n is 0). Preferred R₂groups include hydrogen, alkyl groups having 1 to 4 carbon atoms (i.e.,methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, andcyclopropylmethyl), methoxyethyl, and ethoxymethyl. For substitutedgroups such as substituted alkyl or substituted aryl groups, preferredsubstituents include halogen, nitrile, nitro, carboxy, methoxy,methylthio, trifluoromethyl, and trifluoromethoxy. One or more of thesepreferred substituents, if present, can be present in the compounds ofthe invention in any combination.

[0406] The invention is inclusive of the compounds described herein inany of their pharmaceutically acceptable forms, including isomers (e.g.,diastereomers and enantiomers), salts, solvates, polymorphs, and thelike. In particular, if a compound is optically active, the inventionspecifically includes each of the compound's enantiomers as well asracemic mixtures of the enantiomers.

[0407] Pharmaceutical Compositions and Biological Activity

[0408] Pharmaceutical compositions of the invention contain atherapeutically effective amount of a compound of the invention asdescribed above in combination with a pharmaceutically acceptablecarrier.

[0409] The term “a therapeutically effective amount” means an amount ofthe compound sufficient to induce a therapeutic effect, such as cytokineinduction, antitumor activity, and/or antiviral activity. Although theexact amount of active compound used in a pharmaceutical composition ofthe invention will vary according to factors known to those of skill inthe art, such as the physical and chemical nature of the compound, thenature of the carrier, and the intended dosing regimen, it isanticipated that the compositions of the invention will containsufficient active ingredient to provide a dose of about 10 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg, of thecompound to the subject. Any of the conventional dosage forms may beused, such as tablets, lozenges, parenteral formulations, syrups,creams, ointments, aerosol formulations, transdermal patches,transmucosal patches and the like.

[0410] The compounds of the invention can be administered as the singletherapeutic agent in the treatment regimen, or the compounds of theinvention may be administered in combination with one another or withother active agents, including additional immune response modifiers,antivirals, antibiotics, etc.

[0411] The compounds of the invention have been shown to induce theproduction of certain cytokines in experiments performed according tothe tests set forth below. These results indicate that the compounds areuseful as immune response modifiers that can modulate the immuneresponse in a number of different ways, rendering them useful in thetreatment of a variety of disorders.

[0412] Cytokines whose production may be induced by the administrationof compounds according to the invention generally include interferon-α.(IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds of the invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 andIL-12, and a variety of other cytokines. Among other effects, these andother cytokines can inhibit virus production and tumor cell growth,making the compounds useful in the treatment of viral diseases andtumors. Accordingly, the invention provides a method of inducingcytokine biosynthesis in an animal comprising administering an effectiveamount of a compound or composition of the invention to the animal.

[0413] Certain compounds of the invention have been found topreferentially induce the expression of IFN-α in a population ofhematopoietic cells such as PBMCs (peripheral blood mononuclear cells)containing pDC2 cells (precursor dendritic cell-type 2) withoutconcomitant production of significant levels of inflammatory cytokines.

[0414] In addition to the ability to induce the production of cytokines,the compounds of the invention affect other aspects of the innate immuneresponse. For example, natural killer cell activity may be stimulated,an effect that may be due to cytokine induction. The compounds may alsoactivate macrophages, which in turn stimulate secretion of nitric oxideand the production of additional cytokines. Further, the compounds maycause proliferation and differentiation of B-lymphocytes.

[0415] Compounds of the invention also have an effect on the acquiredimmune response. For example, although there is not believed to be anydirect effect on T cells or direct induction of T cell cytokines, theproduction of the T helper type 1 (Th1) cytokine IFN-γ is inducedindirectly and the production of the T helper type 2 (Th2) cytokinesIL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.This activity means that the compounds are useful in the treatment ofdiseases where upregulation of the Th1 response and/or downregulation ofthe Th2 response is desired. In view of the ability of compounds of theinvention to inhibit the Th2 immune response, the compounds are expectedto be useful in the treatment of atopic diseases, e.g., atopicdermatitis, asthma, allergy, allergic rhinitis; systemic lupuserythematosis; as a vaccine adjuvant for cell mediated immunity; andpossibly as a treatment for recurrent fungal diseases and chlamydia.

[0416] The immune response modifying effects of the compounds make themuseful in the treatment of a wide variety of conditions. Because oftheir ability to induce the production of cytokines such as IFN-α and/orTNF-α, the compounds are particularly useful in the treatment of viraldiseases and tumors. This immunomodulating activity suggests thatcompounds of the invention are useful in treating diseases such as, butnot limited to, viral diseases including genital warts; common warts;plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I andType II; molluscum contagiosum; variola, particularly variola major;rhinovirus; adenovirus; influenza; para-influenza; HIV; CMV; VZV;intraepithelial neoplasias such as cervical intraepithelial neoplasia;human papillomavirus (HPV) and associated neoplasias; fungal diseases,e.g. candida, aspergillus, and cryptococcal meningitis; neoplasticdiseases, e.g., basal cell carcinoma, hairy cell leukemia, Kaposi'ssarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenousleukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneousT-cell lymphoma, and other cancers; parasitic diseases, e.g.pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection, and leishmaniasis; and bacterial infections,e.g., tuberculosis, and mycobacterium avium. Additional diseases orconditions that can be treated using the compounds of the inventioninclude actinic keratosis; eczema; eosinophilia; essentialthrombocythaemia; leprosy; multiple sclerosis; Ommen's syndrome; discoidlupus; Bowen's disease; Bowenoid papulosis; alopecia areata; theinhibition of keloid formation after surgery and other types ofpost-surgical scars. In addition, these compounds could enhance orstimulate the healing of wounds, including chronic wounds. The compoundsmay be useful for treating the opportunistic infections and tumors thatoccur after suppression of cell mediated immunity in, for example,transplant patients, cancer patients and HIV patients.

[0417] An amount of a compound effective to induce cytokine biosynthesisis an amount sufficient to cause one or more cell types, such asmonocytes, macrophages, dendritic cells and B-cells to produce an amountof one or more cytokines such as, for example, IFN-α, TNF-α, IL-1, IL-6,IL-10 and IL-12 that is increased over the background level of suchcytokines. The precise amount will vary according to factors known inthe art but is expected to be a dose of about 100 ng/kg to about 50mg/kg, preferably about 10 μg/kg to about 5 mg/kg.

[0418] The invention also provides a method of treating a viralinfection in an animal and a method of treating a neoplastic disease inan animal comprising administering an effective amount of a compound orcomposition of the invention to the animal. An amount effective to treator inhibit a viral infection is an amount that will cause a reduction inone or more of the manifestations of viral infection, such as virallesions, viral load, rate of virus production, and mortality as comparedto untreated control animals. The precise amount will vary according tofactors known in the art but is expected to be a dose of about 100 ng/kgto about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. An amountof a compound effective to treat a neoplastic condition is an amountthat will cause a reduction in tumor size or in the number of tumorfoci. Again, the precise amount will vary according to factors known inthe art but is expected to be a dose of about 100 ng/kg to about 50mg/kg, preferably about 10 μg/kg to about 5 mg/kg.

[0419] The invention is further described by the following examples,which are provided for illustration only and are not intended to belimiting in any way.

EXAMPLES

[0420] In the examples below some of the compounds were purified usingsemi-preparative HPLC. Two different methods were used and they aredescribed below. Both methods used a A-100 Gilson-6 equipped with 900Series Intelligent Interface. The semi-prep HPLC fractions were analyzedby LC-APCI/MS and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desiredcompound.

[0421] Method A

[0422] Column: column Microsorb C18, 21.4×250 mm, 8 micron particlesize, 60 A pore; flow rate: 10 mL/min.; gradient elution from 2-95% B in25 min., hold at 95% B for 5 min., where A=0.1% trifluoroaceticacid/water and B=0.1% trifluoroacetic acid/acetonitrile; peak detectionat 254 nm for triggering fraction collection.

[0423] Method B

[0424] Column: Phenomenex Capcell PakC18, 35×20 mm, 5 micron particlesize; flow rate: 20 mL/min.; gradient elution from 5-95% B in 10 min.,hold at 95% B for 2 min., where A=0.1% trifluoroacetic acid/water andB=0.1% trifluoroacetic acid/acetonitrile; peak detection at 254 nm fortriggering fraction collection.

Example 1 1-[2-(2-Propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0425]

[0426] Part A

[0427] 2-(1H-Imidazo[4,5-c]quinolin-1-yl)-1-ethanol (28.5 g, 0.133 mol)was added in portions over a period of 1 hour to a mixture of sodiumhydroxide (240 mL of 50%), dichloromethane (240 mL), propargyl bromide(39.6 g of 80%, 0.266 mol) and benzyltrimethylammonium chloride (2.46 g,0.013 mmol). The resulting reaction mixture was allowed to stir atambient temperature for 16 hours. The layers were separated. The aqueousfraction was extracted with additional dichloromethane. The organicfractions were combined, washed with water, dried over magnesium sulfateand then concentrated under reduced pressure. The resulting residue wascombined with diethyl ether and the mixture was allowed to stir. Anorange solid was isolated by filtration. This material wasrecrystallized from ethyl acetate to provide 19.8 g of2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl(2-propynyl) ether as a yellowcrystalline solid, m.p. 124-126° C.

[0428] Analysis. Calculated for C₁₅H₁₃N₃O: % C, 71.70; % H, 5.21; % N,16.72. Found: % C, 71.85; % H, 5.25; % N, 16.90

[0429]¹H NMR (300 MHz, DMSO) δ 9.21 (s, 1H), 8.44 (m, 1H), 8.36 (s, 1H),8.18 (m, 1H), 7.71 (m, 2H), 4.93 (t, J=5.1 Hz, 2H), 4.14 (d, J=2.4 Hz,2H), 3.98 (t, J=5.1 Hz, 2H), 3.35 (t, J=2.2 Hz, 1H)

[0430] HRMS(ESI) Calculated for C₁₅H₁₄N₃O (MH⁺) 252.1137, found 252.1141

[0431] Part B

[0432] 2-(1H-Imidazo[4,5-c]quinolin-1-yl)ethyl(2-propynyl) ether (19.7g, 78.4 mmol) and chloroform were combined and then cooled to 0° C.3-Chloroperoxybenzoic acid (15.7 g of 57-86%) was added and the mixturewas allowed to stir for 0.5 hour. The mixture was allowed to warm toambient temperature by which time all material was in solution. Analysisby thin layer chromatography (TLC) indicated that some starting materialwas still present so more 3-chloroperoxybenzoic acid (two separate 4 gportions) was added. About 0.5 hour after the second portion was added,TLC showed no starting material. The reaction solution was extractedwith 10% sodium hydroxide. The aqueous fraction was then extractedmultiple times with dichloromethane. The organic fractions werecombined, dried over magnesium sulfate, filtered and then concentratedunder reduced pressure to provide 18.5 g of1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide as ayellow oil.

[0433] HRMS(ESI) Calculated for C₁₅H₁₄N₃O₂ (MH⁺) 268.1086, found268.1098

[0434] Part C

[0435] Under a nitrogen atmosphere trichloroacetyl isocyanate (15.5 g,82.2 mmol) was added dropwise to a mixture of1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide (18.3 g,68.5 mmol) and dichloromethane (300 mL). Vigorous carbon dioxideevolution was observed. After about 0.5 hour all of the material was insolution. The reaction solution was allowed to stir for about 1 hour atwhich time analysis by TLC indicated the presence of a small amount ofstarting material. More trichloroacetyl isocyanate (4.5 g) was added.After 1 hour, TLC analysis indicated that the reaction was complete. Thevolatiles were removed under reduced pressure to provideN-{1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-yl}-2,2,2-trichloroacetamideas a pale yellow solid.

[0436] Part D

[0437] Dichloromethane (150 mL) was added to a mixture of the solid fromPart C and methanol (200 mL) and all of the material went into solution.Sodium methoxide (50 g of 25% in methanol) was added and the solutionwas allowed to stir at ambient temperature overnight. The resultingprecipitate was isolated by filtration. The filtrate was concentrated toa volume of approximately 100 mL and a second crop of precipitate wasisolated by filtration. The two crops were combined and dried in avacuum oven at 60° C. for 16 hours to provide 16.4 g of1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as anoff-white solid, m.p. 225-227° C.

[0438] Analysis. Calculated for C₁₅H₁₄N₄O(H₂O)_(1/4): % C, 66.53; % H,5.40; % N, 20.69. Found: % C, 66.33; % H, 5.18; % N, 21.12

[0439]¹H NMR (300 MHz, DMSO) δ 8.13 (s, 1H), 8.08 (br d, J=7.8 Hz, 1H),7.62 (br d, J=8.3 Hz, 1H), 7.44 (br t, J=7.6 Hz, 1H), 7.24 (br t, J=75Hz, 1H), 6.54 (s, 2H), 4.81 (t, J=5.4 Hz, 2H), 4.14 (d, J=2.4 Hz, 2H),3.93 (t, J=5.1 Hz, 2H), 3.38 (t, J=2.4 Hz, 1 H)

[0440] HRMS(ESI) Calculated for C₁₅H₁₅N₄O (MH⁺) 267.1246, found 267.1253

Example 22-{3-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]-1-propynyl}benzonitrile

[0441]

[0442] Part A

[0443] Under a nitrogen atmosphere1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (16 g, 60.1mmol), di-tert-butyl dicarbonate (32.7 g, 150 mmol), triethylamine (21mL, 150 mol), N,N-dimethylformamide (150 mL) and4-(dimethylamino)pyridine (0.1 g) were combined and heated to 80-85° C.After about 1 hour the mixture became homogeneous and TLC analysisindicated that very little starting material remained. The solution washeated for an additional hour. The solution was diluted with ethylacetate and water. The layers were separated and the aqueous fractionwas extracted with ethyl acetate. The organic fractions were combined,washed with water and then with brine, dried over magnesium sulfate,filtered and then concentrated under reduced pressure to provide a paleorange-yellow solid. This material was triturated with diethyl ether toprovide 22.6 g of N,N-(bistert-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas an off-white solid, m.p. 139-142° C.

[0444] Analysis. Calculated for C₂₅H₃₀N₄O₅: % C, 64.36; % H, 6.48; % N,12.01. Found: % C, 64.40; % H, 6.43; % N, 12.06

[0445]¹H NMR (300 MHz, DMSO) δ 8.44 (m, 1H), 8.35 (s, 1H), 8.08 (m, 1H),7.73 (m, 2H), 4.94 (t, J=4.9 Hz, 2H), 4.12 (d, J=2.4 Hz, 2H), 3.98 (t,J=5.1 Hz, 2H), 3.31 (t, J=2.4 Hz, 1H), 1.34 (s, 18H)

[0446] HRMS(ESI) calcd for C₂₅H₃₁N₄O₅ (MH⁺) 467.2294, found 467.2307

[0447] Part B

[0448] Under a nitrogen atmosphere 2-iodobenzonitrile (0.54 g, 2.35mmol), dichlorobis(triphenylphosphine)palladium(II) (0.09 g, 0.13 mmol),and copper(I) iodide (0.05 g, 0.26 mmol) were added to a mixture ofN,N-(bistert-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine(1.0 g, 2.14 mmol) and anhydrous N,N-dimethylformamide (25 mL). After 2hours the reaction mixture was slowly poured into water. The resultingprecipitate was collected and dried at 35° C. for 16 hours to provide1.18 g of 2-(3-{2-[4-(bistert-butoxycarbonyl)amino-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}-1-propynyl)benzonitrileas a solid.

[0449]¹H NMR (300 MHz, DMSO) δ 8.47 (d, J=6.8 Hz, 1H), 8.39 (s, 1H),8.06 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.3 Hz, 1H), 7.40-7.80 (m, 4H), 7.34(d, J=7.3 z, 1H), 5.00 (br s, 2H), 4.47 (br s, 2H), 4.13 (s, 2H), 1.31(s, 18H)

[0450] HRMS(ESI) Calculated for C₃₂H₃₄N₅O₅ (MH⁺) 568.2560, found568.2565

[0451] Part C

[0452] Trifluoroacetic acid (20 mL) was added to a solution of thematerial from Part B in dichloromethane (20 mL). After 4 hours thereaction mixture was diluted with dichloromethane containing a smallamount of methanol and 20% sodium hydroxide. The layers were separated.The aqueous fraction was extracted with dichloromethane. The organicfractions were combined, dried over magnesium sulfate, filtered and thenconcentrated under reduced pressure to provide a yellow powder. Thismaterial was purified by flash chromatography eluting with 9/1dichloromethane/methanol to provide 0.48 g of2-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]-1-propynyl}benzonitrileas a white powder, m.p. 180-183° C.

[0453] Analysis. Calculated for C₂₂H₁₇N₅O(H₂O)_(2/5): % C, 70.54; % H,4.79; % N, 18.70. Found: % C, 70.61; % H, 4.75; % N, 18.70

[0454]¹H NMR (300 MHz, DMSO) δ 8.19 (s, 1H), 8.12 (d, J=8.3 Hz, 1H),7.88 (d, J=7.8 Hz, 1H), 7.55-7.75 (m, 3H), 7.40-7.50 (m, 2H), 7.24 (brt, J=7.5 Hz, 1H), 6.68 (br s, 2H), 4.87 (t, J=5.1 Hz, 2H), 4.50 (s, 2H),4.09 (t, J=5.1 Hz, 2H)

Example 31-{2-[(3-Phenyl-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0455]

[0456] Under a nitrogen atmosphere, a mixture of1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (10 g, 37.6mmol), anhydrous N,N-dimethylformamide (150 mL) and potassium carbonate(6.23 g, 45.1 mmol) was heated to 70° C. Iodobenzene (4.43 mL, 39.5mmol), dichlorobis(triphenylphosphine)palladium(II) (0.53 g, 0.75 mol),and copper(I) iodide (0.29 g, 1.50 mmol) were added and the mixture wasallowed to stir for 0.5 hour. The temperature was raised to about 85° C.After 1.5 hours analysis by HPLC (reverse phase, acetonitrile/water with0.1% trifluoroacetic acid) indicated that the reaction was complete. Themixture was allowed to cool to ambient temperature and then it wasfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified twice by flash chromatography (95/5dichloromethane/methanol) to provide 2.7 g of1-{2-[(3-phenyl-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 196-197° C.

[0457] Analysis. Calculated for C₂₁H₁₈N₄O: % C, 73.67; % H, 5.30; % N,16.36. Found: % C, 73.29; % H, 5.23; % N, 16.35

[0458]¹H NMR (300 MHz, DMSO) δ 8.17 (s, 1H), 8.12 (d, J=7.4 Hz, 1H),7.63 (dd, J 8.3, 0.9 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.15-7.40 (m, 6H),6.60 (s, 2H), 4.86 (t, J=5.1 Hz, 2H), 4.39 (s, 2H), 4.03 (t, J=5.1 Hz,2H)

[0459] HRMS(EI) Calculated for C₂₁H₁₈N₄O (M+) 342.1481, found 342.1490

Example 41-{2-[(3-Phenyl-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineHydrochloride

[0460]1-{2-[(3-Phenyl-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine(1.0 g, 2.92 mmol) was dissolved in a mixture of methanol (15 mL) anddichloromethane (5 mL). Hydrogen chloride/diethyl ether (10 mL of 1M)was added and the reaction solution was allowed to stir for 16 hours bywhich time a precipitate had formed. The mixture was concentrated underreduced pressure to provide a solid. This material was recrystallizedfrom acetonitrile containing a small amount of methanol to provide 0.52g of1-{2-[(3-phenyl-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride as an off-white crystalline solid, m.p. 231-236° C.

[0461] Analysis. Calculated for C₂₁H₁₉ClN₄O.(H₂O)_(1/4): % C, 65.79; %H, 5.13; % N, 14.61. Found: % C, 65.72; % H, 5.0; % N, 14.73

[0462]¹H NMR (300 MHz, DMSO) δ 8.49 (s, 1H), 8.34 (d, J=8.3 Hz, 1H),7.81 (br d, J=8.3 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.56 (t, J=7.8 Hz,1H), 7.30-7.40 (m, 3H), 7.14 (dd, J=8.0, 1.5 Hz, 2H), 4.94 (t, J=4.8 Hz,2H), 4.38 (s, 2H), 4.05 (t, J=4.9 Hz, 2H)

[0463] HRMS (EI) Calculated for C₂₁H₁₈N₄O (M⁺) 342.1481, found 342.1485

Example 5

[0464]1-{2-[3-(4-Methoxyphenyl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0465] Part A

[0466] Under a nitrogen atmosphere, N,N-(bistert-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine(1.0 g, 2.14 mmol), triethylamine (0.8 mL, 5.56 mmol), 4-iodoanisole(0.51 g, 2.18 mmol) and anhydrous N,N-dimethylformamide (15 mL) werecombined. Dichlorobis(triphenylphosphine)palladium(II) (0.09 g, 0.13mol) and copper(I) iodide (0.05 g, 0.26 mmol) were added and thereaction mixture was stirred for 1 hour at ambient temperature at whichtime analysis by HPLC (reverse phase, acetonitrile/water) indicated thatthe reaction was complete. The reaction mixture was partitioned betweenethyl acetate and aqueous sodium bicarbonate. The organic fraction waswashed with water and then with brine, dried over magnesium sulfate,filtered and then concentrated under reduced pressure to provide 0.95 gof N,N-(bistert-butoxycarbonyl)-1-(2-{[3-(4-methoxyphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as an orange solid.

[0467] HRMS(EI) Calculated for C₃₂H₃₆N₄O₆ (M⁺) 572.2635, found 572.2635

[0468] Part B

[0469] N,N-(Bistert-butoxycarbonyl)-1-(2-{[3-(4-methoxyphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine(0.75 g, 1.31 mmol), ethyl acetate (25 mL) and catalyst (100 mg of 5%Pd/C with 50% water) were combined and then hydrogenated on a Parrapparatus at 40 psi (2.8 Kg/cm²). No reaction occurred. Platinum oxide(150 mg) and methanol (10 mL) were added and the mixture washydrogenated at 45 psi (3.15 Kg/cm²) for 1 hour. Hydrogen consumptionwas observed immediately. The reaction mixture was filtered to removethe catalyst. The filtrate was concentrated under reduced pressure toprovide N,N-(bistert-butoxycarbonyl)-1-{2-[3-(4-methoxyphenyl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a yellow-brown gum.

[0470] HRMS(EI) Calculated for C₃₂H₄₀N₄O₆ (M⁺) 576.2948, found 576.2965

[0471] Part C

[0472] Under a nitrogen atmosphere trifluoroacetic acid (10 mL) wasadded to a mixture of the material from Part B and dichloromethane (10mL). The resulting solution was allowed to stir for 4 hours. Thesolution was concentrated under reduced pressure. The residue waspartitioned between 50% aqueous sodium hydroxide and dichloromethanecontaining a small amount of methanol. The organic fraction was driedover magnesium sulfate, filtered and then concentrated under reducedpressure to provide a tan foam. The foam was purified by flashchromatography (9/1 dichloromethane/methanol) to provide a light yellowglass. The glass was triturated with diethyl ether to provide a whitepowder. This material was dried in a vacuum oven for 4 hours at 60° C.to provide 0.41 g of1-{2-[3-(4-methoxyphenyl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 116-118° C.

[0473] Analysis. Calculated for C₂₂H₂₄N₄O₂: % C, 70.19; % H, 6.43; % N,14.88. Found: % C, 69.79; % H, 6.40; % N, 14.73

[0474]¹H NMR (300 MHz, DMSO) δ 8.17 (s, 1H), 8.12 (d, J=8.3 Hz, 1H),7.64 (d, J=8.3 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H),6.80 (d, J=8.8 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 6.60 (s, 2H), 4.80 (t,J=5.1 Hz, 2H), 3.81 (t, J=4.9 Hz, 2H), 3.66 (s, 3H), 3.27 (t, J=6.1 Hz,2H), 2.32 (t, J=7.3 Hz, 2H), 1.60 m, 2H)

Example 6N¹,4-Dimethyl-3-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}-1-benzensulfonamide

[0475]

[0476] Part A

[0477] Under a nitrogen atmosphere,1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.7 g,6.35 mmol), dibenzyl dicarbonate (4.55 g, 15.9 mmol), triethylamine (1.8mL, 13.0 mmol), 4-(dimethylamino)pyridine and anhydrousN,N-dimethylformamide (20 mL) were combined. The reaction mixture washeated to 90° C. at which time the reaction turned homogeneous. It wasthen heated to 130° C. for 4 hours. The reaction mixture was allowed tocool and then it was partitioned between dichloromethane and water. Theaqueous fraction was extracted with dichloromethane. The organicfractions were combined, dried over magnesium sulfate and thenconcentrated to a volume of ˜10 mL. The concentrate was allowed to standover the weekend and then it was diluted with toluene. The resultingprecipitate was isolated by filtration and identified as startingmaterial. The filtrate was diluted with diethyl ether. The resultingprecipitate was isolated by filtration to provide 1.1 g of benzylN-{1-[2-(propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-yl}carbamate asa white solid.

[0478]¹H NMR (300 MHz, DMSO) δ 9.98 (s, 1H), 8.34 (d, J=7.8 Hz, 1H),8.30 (s, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.58 (t,J=7.8 Hz, 1H), 7.15-7.50 (m, 5H), 5.21 (s, 2H), 4.90 (t, J=5.1 Hz, 2H),4.14 (d, J=2.4 Hz, 2H), 3.96 (t, J=4.9 Hz, 2H), 3.38 (t, J=2.4 Hz, 2H)

[0479] Part B

[0480] Under a nitrogen atmosphere benzylN-{1-[2-(propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-yl}carbamate(0.37 g, 0.91 mmol), 3-iodo-4-methyl-1-benzenesulfonamide (0.3 g, 0.96mmol), triethylamine (0.2 mL, 1.36 mmol) and anhydrous acetonitrile (20mL) were combined. Dichlorobis(triphenylphosphine)palladium(II) (13 mg,0.018 mol) and copper(I) iodide (7 mg, 0.036 mmol) were added and thereaction solution was heated to ˜45° C. After 3 hours analysis byreverse phase HPLC indicated that the reaction was complete. Thereaction solution was concentrated under reduced pressure and theresidue was purified by flash chromatography (98/2 to 95/5dichloromethane/methanol) to provide 0.33 g of benzylN-(1-{2-[(3-{2-methyl-5-[(methylamino)sulfonyl]phenyl}-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-yl)carbamateas a pale yellow solid.

[0481]¹H NMR (300 MHz, DMSO) δ 9.96 (s, 1H), 8.36 (m, 2H), 7.96 (d,J=8.3 Hz, 1H), 7.55-7.70 (m, 4H), 7.48 (m, 2H), 7.30-7.45 (m, 5H), 5.21(s, 2H), 4.95 (t, J=4.6 Hz, 2H), 4.40 (s, 2H), 4.06 (t, J=5.1 Hz, 2H),2.54 (s, 3H), 2.40 (d, J=4.9 Hz, 3H) MS (CI) 584,476

[0482] Part C

[0483] Platinum on carbon (0.08 g of 10%) was added to a mixture ofbenzylN-(1-{2-[(3-{2-methyl-5-[(methylamino)sulfonyl]phenyl}-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-yl)carbamate(0.3 g, 0.51 mmol) and methanol (10 mL). The mixture was hydrogenated ona Parr apparatus at 40 psi (2.8 Kg/cm²) for 16 hours. Analysis by LC-MSindicated alkyne reduction but no phenoxycarbonyl removal. Palladium oncarbon (0.1 g of 10%) was added and the reaction mixture washydrogenated at 40 psi (2.8 Kg/cm²) for 8 hours. Analysis by LC-MSindicated only a small amount of phenoxycarbonyl removal. Palladiumblack (0.1 g) was added and the reaction mixture was hydrogenated at 40psi (2.8 Kg/cm²) for 16 hours. Analysis by LC-MS indicated one majorproduct with a mass consistent with the desired product. The reactionmixture was filtered and the filtrate was washed with methanol anddichloromethane. The solvents were removed under reduced pressure toprovide an off-white powder. This material was recrystallized fromacetonitrile to provide 0.11 g ofN¹,4-dimethyl-3-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}-1-benzensulfonamideas a light yellow crystalline solid, m.p. 207-209° C.

[0484] Analysis. Calculated for C₂₃H₂₇N₅O₃S: % C, 60.91; % H, 6.00; % N,15.44. Found: % C, 60.87; % H, 5.75; % N, 15.51

[0485]¹H NMR (300 MHz, DMSO) δ 8.16 (s, 1H), 8.12 (d, J=8.3 Hz, 1H),7.62 (d, J=8.3 Hz, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.44 (br t, J=7.6 Hz,1H), 7.38 (m, 1H), 7.24 (br t, J=7.6 Hz, 1H), 7.16 (d, 7.8 Hz, 1H), 7.02(dd, J=7.8, 2.0 Hz, 1H), 6.58 (s, 2H), 4.80 (t, 5.2 Hz, 2H), 3.82 (t,5.2 Hz, 2H), 3.31 (t, 5.9 Hz, 2H), 2.47 (s, 3H), 2.37 (d, 4.4 Hz, 2H),1.65 (m, 2H)

[0486] HRMS(EI) Calculated for C₂₃H₂₇N₅O₃S (M⁺) 453.1835, found 453.1834

Example 7 1-(2-{[3-(2-Isopropylphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine Hydrochloride

[0487]

[0488] Under a nitrogen atmosphere1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g,1.88 mmol), 2-iodoisopropylbenzene (0.65 g, 2.63 mmol), triethylamine(0.68 mL, 4.88 mmol) and N,N-dimethylformamide (10 mL) were combined andthen heated to 60° C. Copper (I) iodide (0.04 g) anddichlorobis(triphenylphosphine)palladium(II) (0.08 g) were added. After1.5 hours analysis by TLC (9/1 dichloromethane/methanol) indicated thatthe reaction was complete. The reaction mixture was concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 9/1 dichloromethane/methanol. The product fractions werecombined and concentrated under reduced pressure. The residue waspurified by column chromatography eluting with 9/1dichloromethane/methanol containing 0.5% concentrated ammoniumhydroxide. The product fractions were combined and concentrated underreduced pressure to provide ˜0.38 g of a solid. This material wascombined with hydrogen chloride/diethyl ether (3.9 mL of 1.0 M), stirredovernight and then concentrated under reduced pressure. The residue wasrecrystallized from isopropanol/methanol, isolated by filtration andthen dried to provide 0.24 g of1-(2-{[3-(2-isopropylphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride as a solid, m.p. 239-241° C.

[0489] Analysis. Calculated for C₂₄H₂₄N₄O.HCl.(H₂O)_(1/2): % C, 67.06; %H, 6.09; % N, 13.03. Found: % C, 67.07; % H, 6.00; % N, 13.09.

[0490]¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.39 (d, J=8.1 Hz, 1H),7.85 (d, J=8.2 Hz, 1H), 7.76 (t, J=7.2 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H),7.30-7.38 (m, 2H), 7.11-7.19 (m, 2H), 5.00 (t, J=4.7 Hz, 2H), 4.47 (s,2H), 4.10 (t, J=4.7 Hz, 2H), 3.16 (m, 1H), 1.13 (d, J=6.9 Hz, 6H)

[0491] IR (KBr) 3363, 3111, 2957, 1672, 753 cm⁻¹

[0492] HRMS (EI) Calculated for C₂₄H₂₄N₄O (M+) 384.1950, found 384.1943

Example 8 1-(2-{[3-(2,6-Dimethylphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0493]

[0494] Using the general method of Example7,1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g,1.88 mmol) was reacted with 2,6-dimethyl iodobenzene (0.61 g, 2.63mmol). The crude product was purified by column chromatography elutingwith 95/5 dichloromethane/methanol to provide 0.056 g of1-(2-{[3-(2,6-dimethylphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a solid, m.p. 200-201° C.

[0495] Analysis. Calculated for C₂₃H₂₂N₄O.(H₂O)_(2/5): % C, 73.29; % H,6.07; % N, 14.86. Found: % C, 73.36; % H, 5.88; % N, 14.84.

[0496]¹H NMR (300 MHz, DMSO-d₆) δ 8.19 (s, 1H), 8.13 (d, J=8.1 Hz, 1H),7.62 (d, J=7.9 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.23 (t, J=7.9 Hz, 1H),7.09-7.14 (m, 1H), 7.01-7.03 (m, 2H), 6.76 (s, 2H), 4.87 (t, J=4.9 Hz,2H), 4.48 (s, 2H), 4.05 (t, J=4.9 Hz, 2H), 2.15 (s, 6H),

[0497] IR (KBr) 3379, 3065, 1659, 1530, 1483, 1107, 751 cm⁻¹

[0498] HRMS (EI) Calculated for C₂₃H₂₂N₄O (M⁺) 370.1794, found 370.1789.

Example 9 1-(2-{[3-(4-Phenoxyphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0499]

[0500] Using the general method of Example7,1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g,1.88 mmol) was reacted with 4-iodophenyl phenyl ether (0.78 g, 2.63mmol). The crude product was purified by column chromatography elutingwith 95/5 dichloromethane/methanol to provide a solid. The solid wasslurried with aqueous sodium hydroxide to remove salts and then purifiedby column chromatography eluting with 9/1 ethyl acetate/methanol toprovide a solid. This material was further purified by columnchromatography eluting with 99/1 ethyl acetate/methanol to provide 24 mgof 1-(2-{[3-(4-phenoxyphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 146-148° C.

[0501] Analysis. Calculated for C₂₇H₂₂N₄O₂.(H₂O)_(4/5): % C, 72.24; % H,5.30; % N, 12.48. Found: % C, 71.82; % H, 4.85; % N, 12.35.

[0502]¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (s, 1H), 8.12 (d, J=7.4 Hz, 1H),7.62 (d, J=7.7 Hz, 1H), 7.41-7.47 (m, 3H), 7.18-7.27 (m, 4H), 7.06 (dd,J=7.6, 1.0 Hz, 2H), 6.90 (dd, J=6.7 Hz, 2H), 6.71 (s, 2H), 4.85 (t,J=5.1 Hz, 2H), 4.37 (s, 2H), 4.02 (t, J=5.0 Hz, 2H)

[0503] IR (KBr) 3444, 3070, 2928, 1500, 1230, cm⁻¹

[0504] HRMS (EI) Calculated for C₂₇H₂₂N₄O₂ (M+) 434.1743, found434.1748.

Example 10 1-[2-({3-[2-(Trifluoromethyl)phenyl]-2-propynyl}oxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0505]

[0506] Using the general method of Example 7,1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g,1.88 mmol) was reacted with 2-iodobenzotrifluoride (0.71 g, 2.63 mmol).The reaction mixture was concentrated under reduced pressure. Theresulting glassy solid was treated with aqueous sodium bisulfite (10 mL)and methanol (20 mL). A solid was removed by filtration. The filtratewas concentrated under reduced pressure to provide a white powder. Thismaterial was washed with water and dried for 4 days in an oven at 80° C.to provide 0.33 g of a solid. This material was partially dissolved in amixture of dichloromethane (17 mL) and methanol (17 mL). Hydrogenchloride/diethyl ether (3.24 mL of 1.0 M) was added and the mixtureturned homogeneous. The mixture was concentrated under reduced pressureto provide a brown crystalline residue. The residue was combined with50/50 acetonitrile/ethyl acetate containing a small amount of methanol.Sodium hydroxide (0.5 mL of 20%) was added. The mixture was concentratedunder reduced pressure to provide a glassy solid. This glassy solid waspurified by column chromatography eluting with 9/1 ethylacetate/methanol to provide 14 mg of1-[2-({3-[2-(trifluoromethyl)phenyl]-2-propynyl}oxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas a white crystalline solid, m.p. 154-155° C.

[0507] Analysis. Calculated for C₂₂H₁₇F₃N₄O: % C, 64.39; % H, 4.18; % N,13.65. Found: % C, 64.39; % H, 4.19; % N, 13.71

[0508]¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (s, 1H), 8.11 (d, J=7.4 Hz, 1H),7.74 (d, J=7.3 Hz, 1H), 7.56-7.64 (m, 3H), 7.38-7.46 (m, 2H), 7.22 (t,J=7.6 Hz, 1H), 6.59 (s, 2H), 4.87 (t, J=5.1 Hz, 2H), 4.45 (s, 2H), 4.04(t, J=5.1 Hz, 2H)

[0509] IR (KBr) 3375, 3102, 1657, 1583, 1530, 1484, 1320, 1103, 765 cm¹

[0510] HRMS (EI) Calculated for C₂₂H₁₇F₃N₄O (M⁺) 410.1354, found410.1350.

Example 111-(2-{3-[4-(1H-1-Pyrrolyl)phenyl]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-aminetrifluoroacetate

[0511]

[0512] Part A

[0513] Under a nitrogen atmosphere dibenzyl dicarbonate (50 g, 174 mmol)was added to a mixture of1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (16.4 g,61.6 mmol) and anhydrous N,N-dimethylformamide (200 mL). The reactionmixture was allowed to stir at ambient temperature for 16 hours and thereaction mixture turned homogeneous. The reaction mixture waspartitioned between ethyl acetate and water. The layers were separated.The aqueous layer was extracted with ethyl acetate. The organicfractions were combined, washed with water, washed with brine, driedover magnesium sulfate, filtered and then concentrated under reducedpressure to provide a semisolid. This material was triturated withdiethyl ether to provide 27.4 g of N,N-(bisbenzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas a white solid.

[0514] Part B

[0515] Under a nitrogen atmosphere N,N-(bisbenzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine(0.5 g, 0.94 mmol), anhydrous acetonitrile (5 mL), triethylamine (0.34mL, 2.43 mmol), and 1-(4-iodophenyl)pyrrole (0.28 g, 1.03 mmol) werecombined and the resulting homogeneous mixture was heated to 80° C.Copper (I) iodide (0.007 g) anddichlorobis(triphenylphosphine)palladium(II) (0.013 g) were added. Thereaction was complete in 30 minutes. The product was purified by liquidchromatography using 4/6 hexane/ethyl acetate to provide a glassy solid.This material was purified on a second column using 9/1 hexane/ethylacetate to provide 0.229 g of N,N-(bisbenzyloxycarbonyl)-1-[2-({3-[4-(1H-pyrrol-1-yl)phenyl]prop-2-ynyl}oxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine.

[0516]¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (d, J=7.7 Hz, 1H), 8.44 (s, 1H),8.14 (d, J=7.9 Hz, 1H), 7.75-7.77 (m, 2H), 7.54 (d, J=5.1 Hz, 2H), 7.40(s, 2H), 7.32 (d, J=6.8 Hz, 2H), 7.24-7.27 (m, 6H), 7.14-7.16 (m, 4H),6.29 (s, 2H), 5.18 (s, 4H), 5.00 (t, J=5.2 Hz, 2H), 4.42 (s, 2H), 4.10(t, J=5.1 Hz, 2H)

[0517] MS (CI) for C₄₁H₃₃N₅O₅ m/z 676 (MH⁺), 632, 524, 408

[0518] Part C

[0519] The material from Part B, palladium hydroxide (0.24 g of 20% oncarbon) and methanol (5 mL) were combined in a Parr flask andhydrogenated at 45 psi (3.2 Kg/cm²) for 3-4 hours. The reaction mixturewas filtered to remove catalyst, the filter cake was washed withadditional methanol, and the filtrate was concentrated under reducedpressure. The residue was purified by semi-preparative HPLC using MethodB to provide 36.6 mg of1-(2-{3-[4-(1H-1-pyrrolyl)phenyl]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-aminetrifluoroacetate as a solid, m.p. 179-181° C.

[0520] Analysis. Calculated for C₂₅H₂₅N₅O.C₂HF₃O₂: % C, 61.71; % H,4.99; % N, 13.33. Found: % C, 61.49; % H, 4.89; % N, 13.23

[0521]¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.38 (d, J=8.4 Hz, 1H),7.84 (d, J=8.4 Hz, 1H), 7.73 (t, J=7.3 Hz, 1H), 7.56 (t, J=7.8, 1H),7.33 (d, J=8.4 Hz, 2H), 7.26 (t, J=2.1 Hz, 2H), 6.96 (d, J=8.4, 2H),6.24 (t, J=2.1H, 2H), 4.91 (t, J=5.0, 2H), 3.85 (t, J=5.0, 2H), 3.3-3.4(m, 2H), 2.35 (t, J=7.6, 2H), 1.61 (m, 2H),

[0522] IR(KBr) 2949, 1705, 1523, 1204, 1123, 721 cm⁻¹

[0523] HRMS (EI) Calculated for C₂₅H₂₅N₅O (M⁺) 411.2059, found 411.2060.

Example 123-{3-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}benzoicAcid Bis(trifluoroacetate)

[0524]

[0525] Part A

[0526] Under a nitrogen atmosphere N,N-(bistert-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine(2.82 g g, 6.04 mmol), benzyl 3-iodobenzoate (2.245 g, 6.64 mmol),triethylamine (2.2 mL, 15.7 mmol), and anhydrous acetonitrile (20 mL)were combined and the resulting mixture was heated to 60° C. Copper (I)iodide (0.05 g) and dichlorobis(triphenylphosphine)palladium(II) (0.0.08g) were added. The reaction was complete in 30 minutes. The reactionmixture was concentrated under reduced pressure and the residue waspurified by column chromatography eluting initially with dichloromethaneand then with 98/2 dichloromethane/methanol to provide 1.82 g of benzyl3-{3-[2-(4-(bistert-butoxycarbonyl)amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]prop-1-ynyl}benzoate.

[0527]¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d, J=9.6 Hz, 1H), 8.39 (s, 1H),8.05 (d, J=9.8 Hz, 1H), 7.94-7.98 (m, 1H), 7.84 (s, 1H), 7.50-7.70 (m,2H), 7.36-7.49 (m, 7H), 5.36 (s, 2H), 4.98 (t, J=4.6 Hz, 2H), 4.37 (s,2H), 4.06-4.13 (m, 2H), 1.30 (s, 18H) MS(CI) for C₃₉H₄₀N₄O₇ m/z 677(MH⁺), 577, 477

[0528] Part B

[0529] A solution of the material from Part A in methanol was combinedwith catalyst (1.0 g of 10% palladium on carbon) and the mixture washydrogenated at 45 psi (3.2 Kg/cm²) at ambient temperature for ˜2.25hours. More catalyst (0.3 g) was added and the hydrogenation wascontinued for an additional 2 hours. The reaction mixture was filteredto remove the catalyst and the filter cake was rinsed thoroughly withmethanol. The filtrate was concentrated under reduced pressure toprovide 1.2 g of N,N-(bistert-butoxycarbonyl)-3-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}benzoicacid.

[0530]¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d, J=9.5 Hz, 1H), 8.40 (s, 1H),8.07-8.10 (m, 1H), 7.70-7.75 (m, 3H), 7.65 (s, 1H), 1.29 (s, 18H), 7.29(t, J=7.6 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 4.94 (t, J=4.5 Hz, 2H), 3.88(t, J=4.5 Hz, 2H), 3.32 (t, J=6.0 Hz, 2H), 2.43 (t, J=7.0 Hz, 2H), 1.62(m, 2H) MS(CI) for C₃₂H₃₈N₄O₇ m/z 591 (MH⁺), 491, 391

[0531] Part C

[0532] Under a nitrogen atmosphere the material from Part B was combinedwith anhydrous dichloromethane (10 mL) and trifluoroacetic acid (10 mL).The reaction mixture was stirred for 1.5 hours. The reaction mixture wasconcentrated under reduced pressure to provide an oil which was driedunder high vacuum at ambient temperature to give a solid. This solid wastriturated with ether. The resulting white powder was dried at 65° C. ina vacuum oven overnight to provide 1.19 g of3-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-1)ethoxy]propyl}benzoicacid bis(trifluoroacetate), m.p. 138-140° C.

[0533] Analysis. Calculated for C₂₂H₂₂N₄O₃.(C₂HF₃O₂)₂: % C, 50.49; % H,3.91; % N, 9.06. Found: % C, 50.37; % H, 3.67; % N, 9.08

[0534]¹H NMR (300 MHz, DMSO-d₆) δ 9.07-7.14 (bs, 2H), 8.51 (s, 1H), 8.37(d, J=7.8 Hz, 1H), 7.82 (d J=8.0 Hz, 1H), 7.74 (m, 2H), 7.64 (s, 1H),7.56 (t, J=7.1 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H),4.91 (t, J=4.5 Hz, 2H), 3.86 (t, J=4.4 Hz, 2H), 3.34 (t, J=5.9 Hz, 2H),2.44 (t, J=7.4 Hz, 2H), 1.64 (m, 2H)

[0535] IR (KBr) 3367, 3104, 2372, 1685, 1204, 1146 cm⁻¹

[0536] HRMS (EI) Calculated for C₂₂H₂₂N₄O₃ (M+) 390.1692, found390.1690.

Example 132-{3-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}benzoicacid trifluoroacetate

[0537]

[0538] Part A

[0539] Using the general method of Example 12 Part A, N,N-(bistert-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine(2 g, 4.3 mmol) was coupled with benzyl 2-iodobenzoate (1.57 g, 4.71mmol) to provide 1.79 g of a mixture of mono-and di-BOC protected benzyl2-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]prop-1-ynyl}benzoate.

[0540]¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, J=7.9 Hz, 1H), 8.39 (s, 1H),8.06-8.09 (m, i H), 7.85-7.88 (m, 1H), 7.70-7.73 (m, 2H), 7.47-7.51 (m,2H), 7.40-7.43 (m, 2H), 7.28-7.37 (m, 3H), 7.19 (m, 1H), 5.23 (s, 2H),4.97 (t, J=5.0 Hz, 2H), 4.27 (s, 2H), 4.07 (t, J=4.9 Hz, 2H), 1.30 (s,18H) MS(CI) for C₃₉H₄₀N₄O₇ m/Z 677 (MH⁺), 577, 477

[0541] Part B

[0542] Using the general method of Example 12 Part B, the material fromPart A was hydrogenated to provide 0.041 g of a mixture of mono-anddi-BOC protected2-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}benzoicacid.

[0543]¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d, J=7.3 Hz, 1H), 8.39 (s, 1H),8.08 (d, J=7.9 Hz, 1H), 7.71-7.75 (m, 3H), 7.22-7.28 (m, 2H), 6.90 (d,J=7.4 Hz, 1H), 4.93 (t, J=4.6 Hz, 2H), 3.87 (t, J=4.5 Hz, 2H), 3.30 (t,J=5.6 Hz, 2H), 2.73 (t, J=5.7 Hz, 2H), 1.61 (m, 2H), 1.28 (s, 18H)

[0544] MS(CI) for C₃₂H₃₈N₄O₇ m/z 591 (MH⁺), 491, 391

[0545] Part C

[0546] Using the general method of Example 12 Part C, the material fromPart B was hydrolyzed to provide 0.28 g of2-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}benzoicacid as a solid, m.p. 186-188° C.

[0547] Analysis. Calculated for C₂₂H₂₂N₄O₃O₃.C₂HF₃O₂: % C, 57.14; % H,4.59; % N, 11.11. Found: % C, 56.81; % H, 4.47; % N, 11.08

[0548]¹H NMR (300 MHz, DMSO-d₆) δ 8.90-9.20 (bs, 1H), 8.50 (s, 1H), 8.38(d, J=10.1 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.71-7.75 (m, 2H), 7.56 (t,J=7.6 Hz, 1H), 7.21-7.32 (m, 2H), 6.88 (d, J=6.9 Hz, 2H), 4.90 (t, J=4.8Hz, 2H), 3.84 (t, J=4.6 Hz, 2H), 3.32 (m, 2H), 2.72 (t, J=6.9 Hz, 2H),1.62 (m, 2H)

[0549] IR (KBr) 3212, 2929, 1709, 1204, 1124, 747 cm⁻

[0550] HRMS (EI) Calculated for C₂₂H₂₂N₄O₃ (M⁺) 390.1692, found390.1693.

Example 144-{3-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}benzoicAcid Trifluoroacetate

[0551]

[0552] Part A

[0553] Using the general method of Example 12 Part A, N,N-(bistert-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine(2.82 g, 6.04 mmol) was coupled with benzyl 4-iodobenzoate (2.25 g, 6.64mmol) to provide 2.14 g of a mixture of mono-and di-BOC protected benzyl4-[3-(2-{4-amino-1H-imidazo[4,5-c]quinolin-1-yl}ethoxy)prop-1-ynyl]benzoate.

[0554]¹H NMR (300 MHz, DMSO-d₆) δ 8.47 (d, J=7.2 Hz, 1H), 8.40 (s, 1H),8.06 (d, J=6.5 Hz, 1H), 7.87-7.89 (m, 2H), 7.70-7.73 (m, 2H), 7.36-7.49(m, 5H), 7.23-7.27 (m, 2H), 5.35 (s, 2H), 5.0 (t, J=4.5 Hz, 2H), 4.40(s, 2H), 4.09 (t, J=4.5 Hz, 2H), 1.30 (s, 18H)

[0555] MS(CI) for C₃₉H₄₀N₄O₇ m/z 677 (MH⁺), 577, 477

[0556] Part B

[0557] Using the general method of Example 12 Part B, the material fromPart A was hydrogenated to provide 1.86 g of a mixture of mono-anddi-BOC protected4-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}benzoicacid.

[0558]¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (d, J=7.1 Hz, 1H), 8.40 (s, 1H),8.07-8.10 (m, 1H), 7.72-7.75 (m, 4H), 7.01 (d, J=8.4 Hz, 2H), 4.94 (t,J=4.7 Hz, 2H), 3.88 (t, J=4.6 Hz, 2H), 3.30 (m, 2H), 2.38 (t, J=7.3 Hz,2H), 1.62 (m, 2H), 1.29 (s, 18H) MS(CI) for C₃₂H₃₈N₄O₇ m/z 591 (MH⁺),491, 391

[0559] Part C

[0560] Using the general method of Example 12 Part C, the material fromPart B was hydrolyzed to provide 0.96 g of4-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}benzoicacid trifluoroacetate, m.p. 235-237° C.

[0561] Analysis Calculated for C₂₂H₂₂N₄O₃.C₂HF₃O₂: % C, 57.14; % H,4.59; % N, 11.11. Found: % C, 57.06; % H, 4.47; % N, 11.03

[0562]¹H NMR (300 MHz, DMSO-d₆) δ 9.00-9.11 (bs, 2H), 8.51 (s, 1H), 8.37(d, J=8.4 Hz, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.71-7.76 (m, 3H), 7.55 (tJ=9.7 Hz, 1H), 7.01 (d, J=8.2 Hz, 2H), 4.91 (t, J=5.0 Hz, 2H), 3.84 (t,J=4.7 Hz, 2H), 3.32 (t, J=5.8 Hz, 2H), 2.38 (t, J=7.1 Hz, 2H), 1.62 (m,2H)

[0563] IR (KBr) 3266, 3014, 2361, 1667, 1277, 1201, 1142 cm⁻¹

[0564] HRMS (EI) Calculated for C₂₂H₂₂N₄O₃ (M+) 390.1692, found390.1697.

Example 15 1-(2-{3-[3-(Dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride

[0565]

[0566] Part A

[0567] Using the general method of Example 12 Part A, except that thereaction temperature was raised to 80° C., N,N-(bistert-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine(3 g, 6.43 mmol) was coupled with 3-iodo-N,N-dimethylaniline (7.07 mmol)to provide 3.06 g of a mixture of mono protected and unprotected1-[2-({3-[3-(dimethylamino)phenyl]prop-2-ynyl}oxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine.

[0568] Part B

[0569] Using the general method of Example 12 Part B, the material fromPart A was hydrogenated to provide ˜2.9 g of a mixture of mono Bocprotected and unprotected 1-(2-{3-[3-(dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine.

[0570] Part C

[0571] The material from Part B was combined with hydrogenchloride/methanol (30 mL of 3 M) and stirred at ambient temperature for19 hours. A precipitate was removed by filtration. The filtrate wasconcentrated under reduced pressure and the residue was dissolved in asmall amount of methanol and then neutralized with concentrated ammoniumhydroxide to pH ˜11. The resulting precipitate was purified by columnchromatography eluting with 95/5/1 dichloromethane/methanol/ammoniumhydroxide. This material was combined with hydrogen chloride/diethylether. The resulting solution was concentrated under reduced pressure.The residue was triturated with diethyl ether. The resulting solid wasisolated by filtration and then dried to provide 0.114 g of1-(2-{3-[3-(dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride, m.p. 180-183°C.

[0572] Analysis. Calculated for C₂₃H₂₇N₅O.(HCl)_(2.1).(H₂O)_(2.1): % C,54.82; % H, 6.66; % N, 13.89. Found: % C, 54.60; % H, 6.50; % N, 13.66

[0573]¹H NMR (300 MHz, DMSO-d₆) δ 8.71-8.73 (bs, 2H), 8.44 (s, 1H), 8.35(d, J=7.4 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.55(t, J=6.8 Hz, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 6.96 (s, 1H), 6.66 (d,J=8.1 Hz, 1H), 4.88 (t, J=5.3 Hz, 2H), 4.02 (t, J=3.7 Hz, 2H), 3.37 (t,J=6.4 Hz, 2H), 2.94 (s, 6H), 2.40 (t, J=7.6 Hz, 2H), 1.66 (m, 2H),

[0574] IR (KBr) 3426, 3138, 2928, 1693, 1113 cm⁻¹

[0575] HRMS (E1) Calculated for C₂₃H₂₇N₅O (M⁺) 389.2216, found 389.2217

Example 162-(Ethoxymethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineHydrochloride

[0576]

[0577] Part A

[0578] 2-[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (3.50g, 12.9 mmol) was slowly added over a period of 20 minutes to asuspension of sodium hydride (0.67 g of 60% in mineral oil, 16.77 mmol)in anhydrous N,N-dimethylformamide. The reaction mixture was allowed tostir for 1 hour and then 1-bromo-3-phenylpropane (2.16 mL, 14.19 mmol)was added. The reaction mixture was stirred overnight. The reactionmixture was diluted with ethyl acetate, washed with water, washed withbrine, dried over magnesium sulfate, filtered and then concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate to provide 2.38 g of2-(ethoxymethyl)-1-[2-(3-phenylpropxy)ethyl]-1H-imidazo[4,5-c]quinolineas a yellow oil. MS(CI) for C₂₄H₂₇N₃O₂ m/z 390 (MH+), 346.

[0579] Part B

[0580] The material from Part A was combined with chloroform (50 mL) andcooled to 0° C. 3-chloroperoxybenzoic acid (2.22 g of 57-86%) was added.After 1 hour the reaction mixture was allowed to warm to ambienttemperature. The reaction mixture was partitioned between aqueous sodiumbicarbonate and dichloromethane. The organic fraction was dried overmagnesium sulfate, filtered and then concentrated under reduced pressureto provide2-(ethoxymethyl)-1-[2-(3-phenylpropxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxideas a brown solid.

[0581] Part C

[0582] Under a nitrogen atmosphere trichloroacetyl isocyanate (0.87 mL,7.33 mmol) was slowly added to a mixture of the material from Part B andanhydrous dichloromethane (60 mL). After 1 hour the reaction mixture wasconcentrated under reduced pressure to provide2,2,2-trichloro-N-{2-(ethoxymethyl)-1-[2-(3-phenylpropxy)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}acetamide.

[0583] Part D

[0584] Sodium methoxide (4.79 mL of 25% in methanol) was added to amixture of the material from Part C and methanol (30 mL). The reactionmixture was allowed to stir overnight and then it was concentrated underreduced pressure to provide a dark oil. The dark oil was purified bycolumn chromatography eluting with 5% methanol in dichloromethane toprovide a light yellow oil. The oil was treated with 1.0 M hydrogenchloride to provide a white solid. The material was isolated byfiltration and then dried overnight in a vacuum oven at 80° C. toprovide 0.79 g of2-(ethoxymethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride as a white solid, m.p. 128-134° C. Analyzed for C₂₄H₂₈N₄O₂1.55 HCl: % C, 62.53; % H, 6.46; % N, 12.15; Found: % C, 62.64; % H,6.47; % N, 11.91.

[0585]¹H-NMR (300 MHz, DMSO-d₆) δ 8.14 (br d, J=8.3 Hz, 1H), 7.63 (dd,J=8.3, 1.0 Hz, 1H), 7.45 (m, 1H), 7.24 (m, 1H), 7.05-7.15 (m, 3H), 6.90(m, 2H), 6.62 (s, 2H), 4.80-4.90 (m, 4H), 3.83 (t, J=5.4 Hz, 2H), 3.56(q, J=7.0 Hz, 2H), 3.27 (t, J=6.1 Hz, 2H), 2.37 (t, J=7.6 Hz, 2H), 1.63(m, 2H), 1.16 (t, J=6.8 Hz, 3H)

[0586] IR (KBr) 3267, 3023, 1681, 1108 cm¹

[0587] HRMS (EI) Calculated for C₂₄H₂₈N₄O₂ (M⁺) 404.2212, found404.2215.

Example 171-(1-{[(3-Chlorobenzyl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0588]

[0589] Part A

[0590] 2-Ethyl-2-(1H-imidazo[4,5-c]quinolin-1-yl)-1-ethanol (3.0 g,12.43 mmol), dichloromethane (40 mL), aqueous sodium hydroxide (40 mL of50%), benzyltrimethylammonium chloride (0.01 g) and 3-chlorobenzylbromide (2.81 g, 13.67 mmol) were combined and the resulting solutionwas stirred at ambient temperature overnight. Analysis by TLC (5%methanol in dichloromethane) indicated that the reaction was complete.The reaction was diluted with dichloromethane (100 mL) and water (100mL). The layers were separated. The aqueous fraction was extracted withdichloromethane. The organic fractions were combined, washed with brine,dried over magnesium sulfate and then concentrated under reducedpressure. The residue was purified by flash chromatography (silica geleluting with ethyl acetate) to provide 4.22 g of1-(1-{[(3-chlorobenzyl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinoline asa light orange oil.

[0591]¹H-NMR (300 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.63 (s, 1H), 8.55 (d,J=7.8 Hz, 1H), 8.17 (dd, J=7.8, 1.5 Hz, 1H), 7.69 (m, 2H), 7.23 (dd,J=4.9, 1.5 Hz, 2H), 7.08 (s, 1H), 7.03 (m, 1H), 5.40 (m, 1H), 4.47 (s,2H), 3.34-4.07 (m, 2H), 2.11 (m, 2H), 0.88 (t, 7.3 Hz, 3H) MS(CI) forC₂₁H₂₀ClN₃O m/z 366 (MH⁺), 332

[0592] Part B

[0593] 3-Chloroperoxy benzoic acid (2.84 g of 77%) was added in portionsto a solution of the material from Part A in chloroform (60 mL). After 2hours analysis by TLC (10% methanol in dichloromethane) indicated thatthe reaction was complete. The reaction was diluted with chloroform,washed with saturated sodium bicarbonate, washed with brine, dried overmagnesium sulfate and then concentrated under reduced pressure toprovide crude1-(1-{[(3-chlorobenzyl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinolin-5N-oxide.

[0594] Part C

[0595] Ammonium hydroxide (20 mL) was added to a solution of thematerial from Part B in dichloromethane (80 mL). Tosyl chloride (2.42 g)was added in portions. Analysis by TLC (5% methanol in dichloromethane)indicated that the reaction went to completion immediately after theaddition of the tosyl chloride. The reaction mixture was diluted withdichloromethane and saturated sodium bicarbonate. The layers wereseparated. The organic layer was washed with brine, dried over magnesiumsulfate and then concentrated under reduced pressure to provide a lightbrown oil. The oil was purified by flash chromatography (silica geleluting with 5% methanol in dichloromethane) to provide an off-whitegooey solid. This material was purified by flash chromatography (silicagel eluting with 5% methanol in dichloromethane) to provide apinkish-white solid. This material was further purified by flashchromatography (silica gel eluting with ethyl acetate) to provide ˜1.0 gof1-(1-{[(3-chlorobenzyl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinolin-4-amineas an off-white solid, m.p. 60-62° C. Analysis: Calculated forC₂₁H₂₁ClN₄O.¼H₂O: % C, 65.41: % H, 5.62; % N, 14.54; Found: % C, 65.5; %H, 5.62; % N, 14.61.

[0596]¹H-NMR (300 MHz, DMSO-d₆) δ 8.37 (s, 1H), 8.19 (d, J=8.3 Hz, 1H),7.62 (dd, J=8.3, 1.5 Hz, 1H), 7.43 (dt, J=8.3, 1.5 Hz, 1H), 7.18-7.28(m, 3H), 7.09 (m, 1H), 6.52 (br s, 2H), 5.24 (m, 1H), 4.48 (s, 2H), 4.01(dd, J=10.5, 6.6 Hz, 2H), 3.92 (dd, J=10.3, 4.4 Hz, 2H), 2.10 (quintet,J=7.3 Hz, 2H), 0.88 (t, 7.3 Hz, 3H)

[0597] MS(CI) for C₂₁H₂₁ClN₄O m/z 381 (MH⁺), 185

Example 181-{2-[3-(2-Aminophenyl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineTrifluoroacetate

[0598]

[0599] Part A

[0600] Under a nitrogen atmosphere, N,N-(bistert-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine(0.50 g, 1.07 mmol), triethylamine (0.39 mL, 2.79 mmol)) and anhydrousacetonitrile (10 mL) were combined. The resulting solution was heated to80° C. As the reaction was heating, 2-iodoaniline (0.26 mL, 1.18 mmol),copper (I) iodide (0.012 g) anddichlorobis(triphenylphosphine)palladium(II) (0.023 g) were added. Thereaction mixture was heated at 80° C. overnight. The acetonitrile wasremoved under reduced pressure and the residue was purified by flashchromatography (silica gel eluting with 3% methanol in dichloromethane)to provide 0.47 g of N,N-(bistert-butoxycarbonyl)-1-(2-{[3-(2-aminophenyl)prop-2-ynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a brown solid.

[0601]¹H-NMR (300 MHz, DMSO-d₆, D₂O) δ 8.47 (d, J=3.6 Hz, 1H), 8.37 (s,1H), 8.10 (d, J=9.6 Hz, 1H), 7.75 (m, 2H), 7.04 (t, J=7.2 Hz, 1H), 6.80(m, 1H), 6.65 (d, J=8.3 Hz, 1H), 6.45 (t, J=7.3 Hz, 1H), 4.98 (t, J=4.4Hz, 2H), 4.36 (s, 2H), 4.08 (t, J=4.9 Hz, 2H), 1.31 (s, 18H)

[0602] Part B

[0603] Catalyst (5% platinum on carbon) was added to a solution ofN,N-(bis tert-butoxycarbonyl)-1-(2-{[3-(2-aminophenyl)prop-2-ynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine in methanol. The mixture washydrogenated on a Parr apparatus at 50 psi (3.5 Kg.cm²) overnight. Thereaction mixture was filtered through a layer of Celite® filter aid andthe filter cake was washed with additional methanol. The filtrate wasconcentrated under reduced pressure to provide an off-white solid. Thismaterial was purified by flash chromatography (silica gel eluting withdichloromethane, then with 1% methanol in dichloromethane, then with 2%methanol in dichloromethane and finally with 0.3% methanol indichloromethane) to provide ˜0.25 g of N,N-(bistert-butoxycarbonyl)-1-{2-[3-(2-aminophenyl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a light yellow oil.

[0604]¹H-NMR (300 MHz, DMSO-d₆) δ 8.23 (dd, J=8.4, 0.9 Hz, 1H), 8.16(dd, J=8.4, 0.9 Hz, 1H), 7.97 (s, 1H), 6.96 (dt, J=7.5, 1.6 Hz, 2H),6.87 (dd, J=7.5, 1.4 Hz, 1H), 6.62 (dt, J=7.3, 1.0 Hz, 1H), 6.57 (dd,J=8.3, 1.1 Hz, 1H), 5.29 (s, 1H), 4.71 (t, J=5.3 Hz, 2H), 3.91 (t, J=5.1hZ, 2H), 3.38 (t, J=6.0 Hz, 2H), 2.39 (t, J=7.4 Hz, 2H), 1.76 (m, 2H),1.41 (br s, 18H)

[0605] MS(CI) for C₃₁H₃₉N₅O₅ m/z 562 (MH⁺), 462, 362, 229

[0606] Part C

[0607] A solution of the material from Part B in anhydrousdichloromethane (4 mL) was added with stirring to a solution oftrifluoroacetic acid (2 mL) and anhydrous dichloromethane (2 mL) whichhad been cooled to 0° C. The reaction mixture was kept in an ice bathfor about 2 hours and then it was allowed to warm to ambienttemperature. The reaction mixture was stirred at ambient temperatureovernight. The volatiles were removed under reduced pressure to providea pink oil. The oil was dissolved in ethyl acetate (˜3 mL) andtriethylamine (˜1 mL) was added dropwise. The mixture was allowed tostir for about an hour. The resulting precipitate was isolated byfiltration to provide 0.13 g of1-{2-[3-(2-aminophenyl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-aminetrifluoroacetate as a white solid. Analysis: Calculated forC₂₁H₂₃N₅O.C₂HF₃O₂: % C, 58.10; % H, 5.09; % N, 14.73; Found: % C, 57.78;% H, 4.97; % N, 14.59.

[0608]¹H-NMR (300 MHz, DMSO-d₆) δ 8.87 (br s, 1H), 8.49 (s, 1H), 8.36(d, J=7.8 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.72 (t, J=7.3 Hz, 1H), 7.56(t, J=7.6 Hz, 1H), 6.81 (t, J=7.6 Hz, 1H), 6.51 (m, 2H), 6.32 (t, J=6.8Hz, 1H), 4.90 (t, J=4.6 Hz, 2H), 3.85 (t, J=4.9 Hz, 2H), 3.33 (t, J=6.1Hz, 2H), 2.22 (t, J=7.3 Hz, 2H), 1.55 (m, 2H)

[0609] IR (KBr) 3414, 3335, 3253, 3019, 1738, 1202, 1185, 1131 cm⁻¹

[0610] HRMS (EI) Calculated for C₂₁H₂₃N₅O (M+) 361.1903, found 361.1903

Example 194-{[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]methyl}benzonitrile

[0611]

[0612] Part A

[0613] 2-(1H-Imidazo[4,5-c]quinolin-1-yl)ethanol (1.5 g, 7.0 mmol) wasadded to a stirring mixture of α-bromo-p-tolunitrile (1.79 g, 9.1 mmol),sodium hydroxide (20 ml, 50%), dichloromethane (20 ml), andbenzyltrimethylammonium chloride (0.06 g, 0.3 mmol). The reaction wasmaintained for 18 hours and then diluted with dichloromethane (20 ml)and water (20 ml). The two phases were separated and the aqueousfraction was extracted with additional dichloromethane. The organicfractions were combined, washed with water, dried (MgSO₄), filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel, 9/1 dichloromethane/methanol) to provide 1.8 g of4-{[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]methyl}benzonitrile.

[0614]¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.41 (s, 1H), 8.40 (d,J=1.1 Hz, 1H), 8.17 (dd, J=8.3, 1.2 Hz, 1H), 7.72 (dt, J=7.6, 1.3 Hz,1H), 7.66 (dt, J=7.6, 1.3 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.25 (d,J=8.2 Hz, 2H), 4.97 (t, J=5.1 Hz, 2H), 4.53 (s, 2H), 3.97 (t, J=5.5 Hz,2H);

[0615] MS(CI) m/e 329 (M+H).

[0616] Part B

[0617] 3-Chloroperoxybenzoic acid (1.6 g, 5.5 mmol, 60% by weight) wasslowly added to a solution of4-{2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]methyl}benzonitrile (1.8 g,5.5 mmol) in chloroform (50 ml). The reaction was maintained overnightand then sequentially washed with saturated sodium bicarbonate (200 ml),water (2×100 ml), dried (MgSO₄), filtered, and concentrated to provide1.4 g of1-{2-[(4-cyanobenzyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxide.

[0618] Part C

[0619] Trichloroacetyl isocyanate (0.73 ml, 6.1 mmol) was added dropwiseto a solution of1-{2-[(4-cyanobenzyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxide (1.4g, 4.1 mmol) and dichloromethane (25 ml). The reaction was maintainedovernight and then concentrated. The resulting red solid was dissolvedin methanol (100 ml) and sodium methoxide (4 ml, 25% in methanol) wasadded dropwise. The reaction was maintained overnight. The crude productformed as a precipitate and was isolated by filtration. Purification ofthe solid by recrystallization (isopropyl alcohol) followed by flashcolumn chromatography (silica gel, 9/1 dichloromethane/methanol)provided 1.0 g of4-{[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]methyl}benzonitrileas a white solid, m.p. 238.1-239.2° C.

[0620]¹H NMR (300 MHz, DMSO-d₆) δ 8.19 (s, 1H), 8.07 (dd, J=8.2, 1.0 Hz,1H), 7.67 (d, J=8.4 Hz, 2H), 7.62 (dd, J=8.4, 1.1 Hz, 1H), 7.43 (dt,J=7.6, 1.3 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.21 (dt, J=7.6, 1.3 Hz,1H), 6.56 (s, 2H), 4.86 (t, J=5.1 Hz, 2H), 4.55 (s, 2H), 3.93 (t, J=5.1Hz, 2H);

[0621] IR (KBr) 3456, 3285, 3117, 3069, 2228, 1637, 1583, 1526, 1481,1397, 1372, 1353, 1252, 1097, 884, 822, 760 cm⁻¹;

[0622] MS(EI) m/e 343.1440 (343.1433 Calculated for C₂₀H₁₇N₅O);

[0623] Analysis: Calculated for C₂₀H₁₇N₅O: % C, 69.96; % H, 4.99; % N,20.39. Found: % C, 70.09; % H, 4.90; % N, 20.16.

Example 20 2-(Ethoxymethyl)-1-(2-{[6-(4-phenylbutoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline-4-amine

[0624]

[0625] Part A

[0626] A solution of2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (1.0 g, 3.7mmol) in N,N-dimethylformamide (20 ml) was added dropwise to asuspension of sodium hydride (0.19 g of a 60% dispersion in mineral oil,4.8 mmol) in N,N-dimethylformamide (10 ml). The reaction was maintainedfor 45 minutes followed by the dropwise addition of{4-[(6-bromohexyl)oxy]butyl}benzene (1.6 g, 5.1 mmol). The reaction wasstirred overnight at room temperature and then partitioned between ethylacetate and water. The two phases were separated and the aqueousfraction was extracted with additional ethyl acetate. The organicfractions were combined, washed with water, dried (MgSO₄), filtered, andconcentrated. The crude product was purified by flash columnchromatography (silica gel, 4:1 ethyl acetate/hexanes) to provide 0.81 gof 2-(ethoxymethyl)-1-(2-{[6-(4-phenylbutoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline as a brown oil.

[0627] Part B

[0628] 3-Chloroperoxybenzoic acid (0.47 g, 1.6 mmol, 60% by weight) wasslowly added to a solution of2-(ethoxymethyl)-1-(2-{[6-(4-phenylbutoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline (0.81 g, 1.6 mmol) in chloroform (15ml). The reaction was maintained overnight and then sequentially washedwith saturated sodium bicarbonate and water, dried (MgSO₄), filtered,and concentrated to provide 0.7 g of2-(ethoxymethyl)-1-(2-{[6-(4-phenylbutoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-5N-oxideas an orange solid.

[0629] Part C

[0630] Trichloroacetyl isocyanate (0.25 ml, 2.1 mmol) was added dropwiseto a solution of 2-(ethoxymethyl)-1-(2-{[6-(4-phenylbutoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-5N-oxide (0.7 g, 1.4 mmol) anddichloromethane (20 ml). The reaction was maintained for 2 hours andsodium methoxide (2.5 ml, 25% in methanol) was added dropwise. Thereaction was maintained overnight. The mixture was filtered and thefiltrate concentrated. Purification of the filtrate by flash columnchromatography (silica gel, 97:3 ethyl acetate/methanol) provided 0.22 gof2-(ethoxymethyl)-1-(2-{[6-(4-phenylbutoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline-4-amineas a colorless oil.

[0631]¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (d, J=7.9 Hz, 1H), 7.62 (d, J=7.9Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 7.28-7.12 (m, 6H), 6.55 (s, 2H), 4.79(broad s, 4H), 3.82 (t, J=5.3 Hz, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.33-3.22(m, 6H), 2.56 (t, J=7.2 Hz, 2H), 1.62-1.33 (m, 8H), 1.18-1.10 (m, 7H);

[0632] MS(EI) m/e 518.3263 (518.3256 Calculated for C₃₁H₄₂N₄O₃);

[0633] Analysis: Calculated for C₃₁H₄₂N₄O₃: % C, 71.78; % H, 8.16; % N,10.80. Found: % C, 71.20; % H, 8.39; % N, 10.68.

Example 21

[0634]1-{2-[3-(Benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0635] A solution of2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (1.0 g, 3.7mmol) in N,N-dimethylformamide was added dropwise to a suspension ofsodium hydride (0.19 g of a 60% dispersion in mineral oil, 4.8 mmol) inN,N-dimethylformamide (20 ml). The reaction was maintained for 2 hoursfollowed by the dropwise addition of benzyl 3-bromopropyl ether (0.72ml, 4.1 mmol). The reaction was stirred overnight at 100° C., quenchedby pouring over ice, and extracted with ethyl acetate. The organicfractions were washed with water, dried (MgSO₄), filtered, andconcentrated. The crude product was purified by flash columnchromatography (silica gel, 4:1 ethyl acetate/hexanes) to provide 0.45 gof1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolineas a brown oil

[0636]1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolinewas converted to1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amineusing the general methods described in Parts B and C of Example20.Purification by flash column chromatography (silica gel, 95/5 ethylacetate/methanol) provided the desired product as a colorless oil.

[0637]¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (dd, J=8.2, 0.8 Hz, 1H), 7.62(dd, J=8.3, 1.2 Hz, 1H), 7.44 (dt, J=7.6, 1.2 Hz, 1H), 7.32-7.19 (m,6H), 6.56 (s, 2H), 4.85-4.77 (m, 4H), 4.26 (s, 2H), 3.84 (t, J=5.4 Hz,2H), 3.54 (q, J=7.0 Hz, 2H), 3.40 (t, J=6.2 Hz, 2H), 3.26 (t, J=6.2 Hz,2H), 1.63 (pentet, J=6.3 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H);

[0638]¹³C NMR (125 MHz, DMSO-d₆) δ 152.0, 149.5, 145.2, 138.5, 133.3,128.1, 127.4, 127.3, 126.8, 126.3, 126.25, 121.0, 120.6, 114.8, 71.8,69.0, 67.5, 66.3, 65.4, 64.4, 45.4, 29.4, 14.9;

[0639] IR (KBr) 3305, 174, 2970, 2925, 2864, 1633, 1583, 1533, 1481,1437, 1386, 1099, 754, 737, 698 cm⁻¹;

[0640] MS(EI) m/e 434.2318 (434.2317 Calculated for C₂₅H₃₀N₄O₃).

Example 221-[2-(3-Phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0641]

[0642] According to the general method of Example 20 (Parts A-C),2-(1H-imidazo[4,5-c]quinolin-1-yl)ethanol and (3-bromopropyl)benzenewere combined to provide1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as awhite solid.

[0643]¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (s, 1H), 8.12 (d, J=7.2 Hz, 1H),7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.45 (m, 1H), 7.24 (m, 1H), 7.16-7.08 (m,3H), 6.92-6.89 (m, 2H), 6.60 (s, 2H), 4.81 (t, J=5.1 Hz, 2H), 3.82 (t,J=5.1 Hz, 2H), 3.29 (t, J=6.1 Hz, 2H), 2.38 (m, 2H), 1.63 (m, 2H),1.56-1.25 (m, 8H), 0.88 (t, J=7.2 Hz, 3H);

[0644]¹³C NMR (75 MHz, CDCl₃) δ 151.5, 144.9, 142.6, 141.4, 132.6,128.3, 128.2, 127.4, 127.1, 125.8, 122.2, 119.8, 115.4, 70.4, 68.6,47.6, 32.0, 30.9;

[0645] MS(EI) m/e 347.1882 (347.1872 Calculated for C₂₁H₂₂N₄O).

Example 23 1-(2-{[3-(3,4-Dimethylphenyl)-2-propynyl]oxy}ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0646]

[0647] Under a nitrogen atmosphere,1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.9mmol), copper (I) iodide (0.036 g, 0.2 mmol), 4-iodo-ortho-xylene (0.5g, 2.1 mmol) and pyrrolidine (10 mL) were combined and stirred atambient temperature. Dichlorobis(triphenylphosphine)palladium(II) (0.066g, 0.1 mmol) was added and the reaction mixture was stirred at ambienttemperature for 1 hour. Analysis by TLC (30% methanol in chloroform)indicated that starting material was still present. The reaction mixturewas heated at 65° C. overnight. The pyrrolidine was removed underreduced pressure. The resulting residue was triturated withdichloromethane containing methanol. The insoluble material was isolatedby filtration and then recrystallized from toluene (40 mL) to provide0.1 g of1-(2-{[3-(3,4-dimethylphenyl)-2-propynyl]oxy}ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas a solid, m.p. 214-216° C. Analysis: Calculated for C₂₃H₂₂N₄O: % C,74.57; % H, 5.99; % N, 15.12; Found: % C, 74.24; % H, 5.98; % N, 15.08.

[0648]¹H-NMR (300 MHz; DMSO-d₆) 8 (ppm) 8.167(s, 1H), 8.112(d, J=7.3 Hz,1H), 7.628(d, J=8.3 Hz, 1H), 7.44(t, J=7.3 Hz, 1H), 7.232(t, J=6.8 Hz,1H), 7.078(d, J=7.8 Hz, 1H), 7.024(s, 1H), 6.952(d, J=7.9 Hz, 1H),6.586(s, 2H), 4.849(t, J=5 Hz, 2H), 4.365(s,2H), 4.015(t,J=5.6 Hz,2H),2.197(s,3H), 2.159(s,3H).

Examples 24-27

[0649] The compounds in the table below were prepared according to thesynthetic method of Reaction Scheme I above using the following generalmethod.

[0650] 2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-ethylethanol (25 mg)was placed in a 2 dram (7.4 mL) vial. Sodium hydride (1.75 eq of 60% inmineral oil) and N,N-dimethylformamide (1 mL) were added. The vial wasplaced on a sonicator for about 10 minutes at ambient temperature toallow the alkoxide to form. The halide (1.75 eq) was added and the vialwas placed back on the sonicator for about 30 to 60 minutes at ambienttemperature. The reaction mixture was analyzed by LC/MS to confirm theformation of the desired product. The reaction mixture was purified bysemi-preparative HPLC. The semi-prep HPLC fractions were analyzed byLC-APCI/MS and the appropriate fractions were combined and lyophilizedto provide the trifluoroacetate salt of the desired product, which wasconfirmed by accurate mass and ¹H NMR. The table below shows thestructure of the free base and the theoretical mass (TM) and themeasured mass (MM). Example Purification Mass Measurement # Structure ofthe Free Base Method (Da.) 24

A TM = 346.1794 MM = 346.1795 25

A TM = 360.1950 MM = 360.1955 26

A TM = 414.1667 MM = 414.1678 27

A TM = 424.0899 MM = 424.0902

Examples 28-41

[0651] The compounds in the table below were prepared according to thesynthetic method of Reaction Scheme I above using the following generalmethod.

[0652] The 4-amino-1H-imidazo[4,5-c]quinolin-1-yl alcohol (25 mg) wasplaced in a 2 dram (7.4 mL) vial. Sodium hydride (1.2 eq of 60% inmineral oil) and N,N-dimethylformamide (1 mL) were added. The vial wasplaced on a sonicator for about 1 hour at 50° C. to allow the alkoxideto form. The halide (1.2 eq) was added and the vial was placed back onthe sonicator for about 1 to 2 hours at 50° C. The reaction mixture wasanalyzed by LC/MS to confirm the formation of the desired product. Thereaction mixture was purified by semi-preparative HPLC. The semi-prepHPLC fractions were analyzed by LC-APCI/MS and the appropriate fractionswere combined and lyophilized to provide the trifluoroacetate salt ofthe desired product, which was confirmed by accurate mass and ¹H NMR.The table below shows the structure of the free base and the theoreticalmass (TM) and the measured mass (MM). Example Purification MassMeasurement # Structure of the Free Base Method (Da.) 28

A TM = 394.1794 MM = 394.1791 29

A TM = 428.1404 MM = 428.1396 30

A TM = 428.1404 MM = 428.1397 31

A TM = 408.1950 MM = 408.1956 32

A TM = 408.1950 MM = 408.1956 33

A TM = 346.1794 MM = 346.1791 34

A TM = 380.1404 MM = 380.1399 35

A TM = 380.1404 MM = 380.1399 36

A TM = 360.1950 MM = 360.1942 37

A TM = 360.1950 MM = 360.1941 38

A TM = 380.1404 MM = 380.1400 39

A TM = 371.1746 MM = 371.1751 40

A TM = 380.1404 MM = 380.1398 41

A TM = 376.1535 MM = 376.1536

Examples 42-88

[0653] The compounds in the table below were prepared according to thesynthetic method of Reaction Scheme I above using the following generalmethod.

[0654] The 4-amino-1H-imidazo[4,5-c]quinolin-1-yl alcohol (25 mg) wasplaced in a 2 dram (7.4 mL) vial. Sodium hydride (1.2 eq of 60% inmineral oil) and N,N-dimethylformamide (1 mL) were added. The vial wasplaced on a sonicator for about 15 to 30 minutes at ambient temperatureto allow the alkoxide to form. The halide (1.2 eq) was added and thevial was placed back on the sonicator for about 15 to 120 minutes atambient temperature. The reaction mixture was analyzed by LC/MS toconfirm the formation of the desired product. The reaction mixture waspurified by semi-preparative HPLC. The semi-prep HPLC fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desired product,which was confirmed by accurate mass and ¹H NMR. The table below showsthe structure of the free base and the theoretical mass (TM) and themeasured mass (MM) or nominal mass (NM). Example Purification MassMeasurement # Structure of the Free Base Method (Da.) 42

A TM = 318.1481 MM = 318.1482 43

A TM = 328.1535 MM = 328.1534 44

A TM = 377.1488 MM = 377.1487 45

A TM = 430.1617 MM = 430.1614 46

A TM = 371.1746 MM = 371.1746 47

A TM = 380.1404 MM = 380.1394 48

A TM = 430.1617 MM = 430.1613 49

A TM = 360.1950 MM = 360.1949 50

A TM = 346.1794 MM = 346.1781 51

A TM = 363.1331 MM = 363.1324 52

A TM = 366.1247 MM = 366.1243 53

A TM = 400.0858 MM = 400.0856 54

A TM = 364.1331 MM = 364.1352 55

A TM = 405.1801 MM = 405.1794 56

A TM = 377.1488 MM = 377.1490 57

A TM = 391.1644 MM = 391.1637 58

A TM = 391.1644 MM = 391.1637 59

A TM = 360.1950 MM = 360.1938 60

A TM = 394.1560 MM = 394.1558 61

A TM = 394.1560 MM = 294.1557 62

A TM = 428.1171 MM = 428.1159 63

A TM = 428.1824 MM = 428.1826 64

A TM = 385.1903 MM = 385.1904 65

A TM = 385.1903 MM = 385.1897 66

A TM = 418.2005 MM = 418.2013 67

A TM = 388.2263 MM = 388.2257 68

A TM = 400.1511 MM = 400.1507 69

A TM = 382.1794 MM = 382.1788 70

A TM = 332.1637 MM = 332.1641 71

A TM = 390.1692 MM = 390.1697 72

A TM = 346.1794 MM = 346.1791 73

A TM = 366.1247 MM = 366.1241 74

A TM = 400.1511 MM = 400.1512 75

A TM = 346.1794 MM = 346.1799 76

A TM = 360.1950 MM = 360.1953 77

A TM = 360.1950 MM = 360.1941 78

A TM = 414.1667 MM = 414.1670 79

A TM = 452 NM [M + H]⁺¹ = 453 80

A TM = 360 NM [M + H]⁺¹ = 361 81

A TM = 360 NM [M + H]⁺¹ = 361 82

A TM = 374 NM [M + H]⁺¹ = 375.2 83

B TM = 379.1281 MM = 379.1278 84

B TM = 348.1586 MM = 348.1588 85

B TM = 362.1743 MM = 362.1736 86

B TM = 362.1743 MM = 362.1748 87

B TM = 373.1539 MM = 373.1546 88

B TM = 373.1539 MM = 373.1543

Examples 89-96

[0655] The compounds in the table below were prepared according to thesynthetic method of Reaction Scheme V above using the following generalmethod.

[0656]2-(4-Amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)ethanol(25 mg) was placed in a 2 dram (7.4 mL) vial. Sodium hydride (1.2 eq of60% in mineral oil) and N,N-dimethylformamide (1 mL) were added. Thevial was placed on a sonicator for about 15 minutes at ambienttemperature to allow the alkoxide to form. The halide (1.2 eq) was addedand the vial was placed back on the sonicator for about 15 minutes atambient temperature. The reaction mixture was analyzed by LC/MS toconfirm the formation of the desired product. The reaction mixture waspurified by semi-preparative HPLC. The semi-prep HPLC fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desired product,which was confirmed by accurate mass and ¹H NMR. The table below showsthe structure of the free base and the theoretical mass (TM) and themeasured mass (MM). Example Purification Mass Measurement # Structure ofthe Free Base Method (Da.) 89

B TM = 412.2030 MM = 412.2023 90

B TM = 392.2576 MM = 392.2575 91

B TM = 446.2293 MM = 446.2287 92

B TM = 446.2293 MM = 446.2288 93

B TM = 403.2372 MM = 403.2365 94

B TM = 403.2372 MM = 403.2370 95

B TM = 434.3046 MM = 434.3047 96

B TM = 409.2114 MM = 409.2117

Examples 97-100

[0657] The compounds in the table below were prepared according to thesynthetic method of Reaction Scheme III above using the followinggeneral method.

[0658] A 1 mL portion of a solution prepared by dissolving 0.5 g of1-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)propan-2-ol inN,N-dimethylformamide (20 mL) was added to a 2 dram (7.4 mL) glass vialcontaining the phenol (2 eq.). Triphenylphosphine (54 mg, 2 eq.)dissolved in N,N-dimethylformamide (1 mL) was added to the vial. Theresulting slurry was sonicated to dissolve the phenol. Diethylazodicarboxylate (36 mg, 2 eq.) was added neat. The reaction mixture wassonicated for about 30 minutes and then shaken overnight at ambienttemperature. The reaction mixture was purified by semi-preparative HPLCusing Method A. The compounds of Examples 99 and 100 were provided asthe trifluoroacetate salts The products were confirmed by accurate massand ¹H NMR. The table below shows the structure of the free base and thetheoretical mass (TM) and the Ex- Mass am- Measure- ple # Structure ment97

TM = 343 NM[M +H]⁺¹ = 344 98

TM = 384 NM[M +H]⁺¹ = 385 99

TM = 348 NM[M +H]⁺¹ = 349 100

TM = 430 NM[M +H]⁺¹ = 431

Examples 101-104

[0659] The compounds in the table below were prepared according to thesynthetic method of Reaction Scheme III above using the followinggeneral method.

[0660] A 1 mL portion of a solution prepared by dissolving 0.5 g of2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-ethylethanol inN,N-dimethylformamide (20 mL) was added to a 4 dram (15 mL) glass vialcontaining the phenol (2 eq.). Triphenylphosphine (51 mg, 2 eq.)dissolved in N,N-dimethylformamide (1 mL) was added to the vial. Diethylazodicarboxylate (34 mg, 2 eq.) was added neat. The resulting solutionwas sonicated for about 2 minutes and then shaken overnight at ambienttemperature. Analysis by HPLC indicated that the reaction was notcomplete. The solvent was removed under vacuum. The resulting oil wasdissolved in 1 mL of tetrahydrofuran containing triphenylphosphine (2eq.). Diethyl azodicarboxylate (2 eq.) was added neat. The reactionmixture was shaken at ambient temperature overnight. Analysis by HPLCindicated that the reaction was complete. The reaction mixture waspurified by semi-preparative HPLC using Method B The semi-prep HPLCfractions were analyzed by LC-APCI/MS and the appropriate fractions werecombined and lyophilized to provide the trifluoroacetate salt of thedesired product, which was confirmed by accurate mass and ¹H NMR. Thetable below shows the structure of the free base and the theoreticalmass (TM) and the nominal mass (NM). Ex- Mass am- Measure- ple #Structure of the Free Base ment 101

TM = 398 NM[M +H]⁺¹ = 399 102

TM = 357 NM[M +H]⁺¹ = 358 103

TM = 444 NM[M +H]⁺¹ = 445 104

TM = 389 NM[M +H]⁺¹ = 390

Example 105 1-(2-Phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0661]

[0662] 2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (25 mg, 0.108mmol) and N,N-dimethylformamide (1 mL) were combined. Phenol (12 mg,0.130 mmol) and triphenylphosphine (34 mg, 0.130 mmol) were added andthe resulting slurry was sonicated for about 1 minute. Diethylazodicarboxylate (23 mg, 0.130 mmol) was added and the reaction mixturewas shaken at ambient temperature for 24 hours. Analysis by LC-MS showedthat a major amount of starting material remained. An additionalequivalent each of phenol, triphenylphosphine and diethylazodicarboxylate were added. The reaction mixture was sonicated for 30minutes. After 1 hour analysis by LC-MS showed product. The solvent wasremoved and the residue was purified by semi-preparative HPLC usingMethod A. Mass Measurement: TM=304, NM[M+H]⁺¹=305.

Example 1061-[(1-Phenoxymethyl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0663]

[0664] 2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-ethylethanol (50 mg,0.195 mmol) and N,N-dimethylformamide (2 mL) were combined. Phenol (37mg, 0.390 mmol) and triphenylphosphine (102 mg) were added followed bydiethyl azodicarboxylate (67 mg, 0.390 mmol). The resulting solution wassonicated for 1 hour. Analysis by LC-MS showed product and a smallamount of starting material. The solvent was removed and the residue waspurified by semi-preparative HPLC using Method A. Mass Measurement:TM=332, NM[M+H]⁺¹=333.

Example 1071-{(1R)-1-[(Prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0665]

[0666] Part A

[0667] Crude 4-chloro-3-nitroquinoline (413.8 g, 1 eq.) was dissolved indichloromethane (1.65 L). The solution was heated to reflux and thenfiltered through a layer of Celite® filter agent. The filtrate wascooled to 5° C. with stirring. Triethylamine (305.4 mL, 1.1 eq.) wasadded in a single portion. The reaction mixture was stirred for 15minutes. (R)-(−)-2-Amino-1-butanol (205 mL, 1.1 eq.) was added dropwisewhile maintaining the temperature of the reaction mixture below 40° C.The reaction mixture was allowed to stir at ambient temperature forseveral days. The reaction mixture was cooled to −30° C. A yellowprecipitate was isolated by filtration, washed with very colddichloromethane and then sucked dry. The solid was slurried for 1 hourwith cold 80/20 water/methanol (1 L), isolated by filtration, washedwith cool water, washed with very cold methanol (2×300 mL), and thensucked dry on the filter overnight to provide 475 g of(2R)-2-[(3-nitroquinolin-4-yl)amino]butan-1-ol.

[0668] Part B

[0669] (2R)-2-[(3-Nitroquinolin-4-yl)amino]butan-1-ol (238 g),isopropanol (5 L) and catalyst (23.8 g of 5% platinum on carbon) werecombined in a stainless steel vessel and hydrogenated at 50 psi (3.5Kg/cm²) for 16 hours. The reaction mixture was filtered through a layerof Celite® filter agent to remove the catalyst. The filtrate wasconcentrated under reduced pressure to provide 208.3 g of(2R)-2-[(3-aminoquinolin-4-yl)amino]butan-1-ol as an amber oil. Thereaction was run a second time on the same scale.

[0670] Part C

[0671] (2R)-2-[(3-Aminoquinolin-4-yl)amino]butan-1-ol (416.0 g, 1 eq.)and triethylorthoformate (1.2 L, 4 eq.) were combined and slowly heatedto 145° C. Ethanol was distilled off as it formed during the reaction.After 500 mL of ethanol had been distilled off, the reaction mixture wasallowed to cool to 50° C. under a nitrogen atmosphere. ExcesstriethyLorthoformate was removed under reduced pressure to provide crude(2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol.

[0672] Part D

[0673] A mixture of (2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol(434.3 g) and acetic anhydride (1.2 L) was slowly heated over a periodof about 2 hours to 100° C. The reaction mixture was allowed to cool toambient temperature overnight. Methanol (2.5 L) was added and thereaction mixture exothermed to produce a vigorous reflux. The reactionmixture was heated at reflux for an additional 2 hours, cooled toambient temperature and then concentrated under reduced pressure. Theresidue was diluted with water and then made basic with sodiumbicarbonate. Analysis of the resulting oil by TLC (20% methanol in ethylacetate) showed two products and no starting material. The oil wasextracted into ethyl acetate. The organic layer was washed with water,dried over magnesium sulfate, filtered and then concentrated underreduced pressure to provide 359.3 g of a residue. This material wascombined with acetic anhydride (1.6 L) and then heated to reflux for 1hour. The reaction mixture was allowed to cool to ambient temperatureovernight and then concentrated under reduced pressure. Analysis of theresidue by TLC showed a single product spot. The residue was dilutedwith water (1 L), made basic (pH 8) with saturated sodium bicarbonatesolution and then stirred for 1 hour. The resulting precipitate wasisolated by filtration, washed with water and then dried in a vacuumoven overnight at 60° C. to provide(2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butyl acetate as a brown solid.

[0674] Part E

[0675] Sodium methoxide (163.0 g of 25% in methanol, 1.1 eq.) was addedin a single portion to a solution of(2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butyl acetate (194.0 g, 1 eq.) inmethanol (970 mL). The reaction mixture was stirred at ambienttemperature for 3 hours and then concentrated under reduced pressure.The residue was diluted with water (1 L), neutralized (pH 6-7) withacetic acid and then stirred at ambient temperature overnight. Theresulting precipitate was isolated by filtration, washed with water(2×200 mL), air dried on the filter and then dried in a vacuum ovenovernight at 50° C. to provide 145.5 g of(2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol as a solid.

[0676] Part F

[0677] (2R)-2-(1H-Imidazo[4,5-c]quinolin-1-yl)butan-1-ol (19 g, 78.8mmol) was added to a mixture of sodium hydroxide (124 mL of 50%),dichloromethane (150 mL), benzyltrimethyl ammonium chloride (0.73 g),and propargyl bromide (11.4 mL, 102 mmol). The reaction mixture wasallowed to stir at ambient temperature overnight. The reaction mixturewas diluted with dichloromethane and water. The aqueous fraction wasextracted multiple times with dichloromethane. The organic fractionswere combined, washed with water, dried over magnesium sulfate, filteredand then concentrated under reduced pressure. The residue was purifiedby column chromatography eluting with ethyl acetate to provide 20.9 g of1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-c]quinoline asa brown liquid.

[0678] Part G

[0679] 3-Chloroperoxybenzoic acid (15.0 g of 57-86%) was added to achilled (0°) mixture of the material from Part F and chloroform (250mL). After 0.5 hour the reaction mixture was allowed to warm to ambienttemperature. The progress of the reaction was monitored by TLC and twoadditional portions of 3-chloroperoxybenzoic acid (3.75 g) were added.When the reaction was complete, it was washed with sodium bicarbonate.The aqueous fraction was extracted with ethyl acetate. The organicfractions were combined, dried over magnesium sulfate, filtered and thenconcentrated under reduced pressure to provide1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-c]quinoline-5N-oxideas a brown oil which solidified overnight.

[0680] Part H

[0681] Trichloroacetyl isocyanate (10.7 mL) was added dropwise to amixture of the material from Part G and anhydrous dichloromethane (300mL). After 1 hour analysis by TLC indicated that the reaction was notcomplete so more trichloroacetyl isocyanate (2 mL) was added. After 1hour the reaction mixture was concentrated under reduced pressure toprovide2,2,2-trichloro-N-(1-{(1R)-1-[(2-propynyloxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-yl)acetamideas a yellow solid.

[0682] Part I

[0683] Sodium methoxide (57.5 mL of 25% in methanol) was added to amixture of the material from Part H and methanol (250 mL). The reactionmixture turned homogeneous after 0.5 hour and was stirred overnight. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography eluting with 80/20dichloromethane/methanol to provide a solid. The solid was washed withdiethyl ether, recrystallized from toluene and then dried in an oven at60° C. overnight to provide 9.77 g of1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amineas a crystalline solid.

[0684]¹H-NMR (300 MHz, DMSO-d₆) δ 8.37 (s, 1H),. 8.19 (d, J=8.3 Hz, 1H),7.65 (dd, J=8.3, 1.5 Hz, 1H), 7.44 (br t, J=7.6 Hz, 1H), 7.25 (br t,J=7.6 Hz, 1H), 6.65 (s, 2H), 5.23 (m, 1H), 4.17 (d, J=2.0 Hz, 2H),3.90-4.10 (m, 2H), 3.46 (t, J=2.4 Hz, 1H), 2.07 (m, 2H), 0.88 (t, J=7.3Hz, 3H).

Example 108

[0685]1-((1R)-1-{[(3-Phenylprop-2-ynyl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0686] Part A

[0687] Under a nitrogen atmosphere1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amine(0.80 g, 1.25 mmol) and anhydrous N,N-dimethylformamide (60 mL) werecombined and then heated to 40° C. Dibenzyl dicarbonate (3.98 g, 13.9mmol) was added. The reaction was monitored by TLC and HPLC. After 2hours more dibenzyl dicarbonate (1 g) was added. After 1 hour thereaction went to completion. The reaction mixture was diluted with ethylacetate, washed with water, washed with brine, dried over magnesiumsulfate, filtered and then concentrated under reduced pressure toprovide N,N-(bisbenzyloxycarbonyl)-1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amineas a light brown oil. The oil was washed with hexane to remove excessdibenzyl dicarbonate.

[0688] Part B

[0689] N,N-(Bisbenzyloxycarbonyl)-1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amine(1.91 g, 3.4 mmol), anhydrous acetonitrile (30 mL) and triethylamine(0.71 mL, 5.1 mmol) were combined and then heated to 70° C. Copper (I)iodide (0.026 g), dichlorobis(triphenylphosphine)palladium(II) (0.048 g)and iodobenzene (0.40 mL, 3.7 mmol) were added. The reaction wascomplete in 0.5 hour. The reaction mixture was diluted with ethylacetate, washed with water, washed with brine, dried over magnesiumsulfate, filtered and then concentrated under reduced pressure toprovide a brown liquid. This material was purified by columnchromatography eluting with 39.5/59.5/1 ethylacetate/hexane/triethylamine to provide 2.1 g of an oil. The oil was amixture of mono and di benzyloxycarbonyl protected1-((1R)-1-{[(3-phenylprop-2-ynyl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinolin-4-amine.

[0690] Part C

[0691] A portion of the material from Part B (0.8 g), methanol, andsodium methoxide (1.0 mL of 25% in methanol) were combined. After 16hours analysis by TLC indicated that the reaction was complete. Thereaction mixture was concentrated under reduced pressure. The resultingoil was purified by column chromatography eluting with 5% methanol indichloromethane to provide a glassy solid. This material was dried underhigh vacuum at ambient temperature overnight to provide 0.3 g of1-((1R)-1-{[(3-phenylprop-2-ynyl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinolin-4-amine,m.p. 63-67° C.

[0692] Analysis:. Calculated for C₂₃H₂₂N₄O: % C, 74.57; % H, 5.99; % N,15.12; Found: % C, 74.18; % H, 6.10; % N, 15.00.

[0693]¹H-NMR (300 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.21 (d, J=8.3 Hz, 1H),7.64 (dd, J=8.5, 1.2 Hz, 1H), 7.43 (br t, J=7.6 Hz, 1H), 7.25-7.40 (m,5H), 7.22 (br t, J=7.6 Hz, 1H), 6.61 (s, 2H), 5.26 (m, 1H), 4.41 (s,2H), 3.95-4.20 (m, 2H), 2.10 (m, 2H), 0.90 (t, J=7.3 Hz, 3H)

[0694] IR (KBr) 3306, 3171, 1634, 1526, 1100, 755 cm⁻¹

[0695] HRMS (EI) Calculated for C₂₃H₂₂N₄O (M⁺) 370.1794, found 370.1798.

Example 1091-{(1R)-1-[(3-Phenylpropoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0696]

[0697] Under a nitrogen atmosphere palladium hydroxide (0.72 g of 20% oncarbon) was added to a solution of material from Example 108 Part B (1.3g) in methanol (˜20 mL). The mixture was hydrogenated at 50 psi (3.5Kg/cm²) for 3.5 hours. The reaction mixture was filtered to remove thecatalyst. The filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography eluting with 2.5% methanolin dichloromethane to provide an oil. The oil was triturated withdiethyl ether to provide a solid which was isolated and dried to provide0.4 g of1-{(1R)-1-[(3-phenylpropoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4-amineas a white crystalline solid, m.p. 118-120° C.

[0698] Analysis: Calculated for C₂₃H₂₆N₄O: % C, 73.77; % H, 7.00; % N,14.96. Found: % C, 73.68; % H, 7.17; % N, 14.72.

[0699]¹H-NMR (300 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.22 (d, J=7.8 Hz, 1H),7.65 (dd, J=8.3, 1.0 Hz, 1H), 7.44 (br t, J=7.7 Hz, 1H), 7.05-7.30 (m,4H), 6.95 (br d, J=6.8 Hz, 2H), 6.62 (s, 2H), 5.20 (m, 1H), 3.88 (m,2H), 3.36 (m, 2H), 2.37 (br t, J=7.6 Hz, 2H), 2.08 (m, 2H), 1.63 (m,2H), 0.89 (t, J=7.3 Hz, 3H)

[0700] IR (KBr) 3458, 3109 1639, 1528, 1392, 1250, 760 cm⁻¹

[0701] HRMS (EI) Calculated for C₂₃H₂₆N₄O (M+) 374.2107, found 374.2104.

Examples 110-112

[0702] Part A

[0703] Triethylamine (15 mL) and R-3-amino-2-methylpropan-1-ol (about0.1 mole of crude) were added to a solution of2,4-dichloro-3-nitroquinoline (24.3 g, 0.1 mole) in dichloromethane (250mL). The reaction mixture was refluxed until analysis by TLC showed nochange. The reaction mixture was evaporated to dryness. The solidyellow-brown residue was crushed and then extracted repeatedly withhexane containing a small amount of dichloromethane in order to removethe starting quinoline. The residue was then recrystallized fromisopropanol to provide 19.0 g ofR-3-[(2-chloro-3-nitroquinolin-4-yl)amino]-2-methylpropan-1-ol as ayellow solid. A sample (500 mg) was recrystallized from isopropanol toprovide a yellow crystalline solid, m.p. 174-176° C.

[0704] Part B

[0705] R-3-[(2-Chloro-3-nitroquinolin-4-yl)amino]-2-methylpropan-1-ol(10 g, 33.8 mmol), isopropanol (350 mL) and catalyst (˜1 g of 5%platinum on carbon) were combined and then hydrogenated on a Parrapparatus at 50 psi (3.5 Kg/cm²) initial hydrogen pressure. Whenhydrogen uptake had ceased, the reaction mixture was filtered to removethe catalyst. The filtrate was evaporated under reduced pressure toprovide crudeR-3-[(3-amino-2-chloroquinolin-4-yl)amino]-2-methylpropan-1-ol.Diethoxymethyl acetate (10.0 mL, 61.5 mmol) was added to the crudeintermediate and a strong heat of reaction was observed. The resultingsolution was heated on a steam bath for 20 minutes and then diluted withwater and ammonium hydroxide. The resulting oil was extracted into ethylacetate. The extracts were combined, dried over magnesium sulfate andthen concentrated under reduced pressure. The resulting solid wasslurried with ethyl acetate/hexane, isolated by filtration, washed withethyl acetate/hexane and then dried to provide 6.0 g of R3-(4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-ol as ayellow/tan solid.

[0706] Part C

[0707] R 3-(4-Chloro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-ol(1.0 g, 3.6 mmol) and methanolic ammonia (30 mL of ˜15%) were combinedand then heated in a steel bomb at 150° C. The container was allowed tocool to ambient temperature. Excess methanolic potassium hydroxide wasadded to the reaction mixture which was then concentrated under reducedpressure to decrease the volume. Water was added and then concentrationwas continued until a solid formed. The solid was isolated byfiltration, washed with water and then dried to provide a near whitesolid. This material was recrystallized from methanol/dichloromethane toprovide R 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-olas colorless solid, m.p. 258-261° C. Analysis:

[0708] Calculated for C₁₄H₁₆N₄O: % C, 65.61, % H, 6.29; % N, 21.86;Found: % C, 65.50, % H, 6.3, % N, 21.7.

[0709] Part D

[0710] The compounds in the table below were prepared according to thesynthetic method of Reaction Scheme I above using the following generalmethod.

[0711] R 3-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-ol(25 mg) was placed in a 2 dram (7.4 mL) vial. Sodium hydride (1.2equivalents of 60% in mineral oil) and N,N-dimethylformamide (1 mL) wereadded. The vial was placed on a sonicator for about 15 minutes at 50° C.to allow the alkoxide to form. The halide (1.2 equivalents) was addedand the vial was placed back on the sonicator for about 2 hours at 50°C. The reaction mixture was analyzed by LC/MS to confirm the formationof the desired product. The reaction mixture was purified bysemi-preparative HPLC. The semi-prep HPLC fractions were analyzed byLC-APCI/MS and the appropriate fractions were combined and lyophilizedto provide the trifluoroacetate salt of the desired product, which wasconfirmed by accurate mass and ¹H NMR. The table below shows thestructure of the free base and the theoretical mass (TM) and themeasured mass (MM). Example Purification Mass Measurement # Structure ofthe Free Base Method (Da.) 110

A TM = 371.1746 MM = 371.1749 111

A TM = 402.2420 MM = 402.2413 112

A TM = 380.1404 MM = 380.1402

Example 113

[0712] 1-[(Benzyloxy)methyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0713] Sodium hydride (0.48 g of 60%, 11.9 mmol) was added to asuspension of 1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 10.9 mmol) inN,N-dimethylformamide. The reaction mixture was stirred at ambienttemperature for 3 hours and then chilled in an ice bath. Benzylchloromethyl ether (1.5 mL, 10.9 mmol) was added. The reaction mixturewas stirred at ambient temperature for 2 hours and then heated on asteam bath for 1 hour. A precipitate was isolated by filtration. Thefiltrate was diluted with water and an oil separated. The oil was seededwith the precipitated solid and 2.1 g of a gummy solid was obtained.This material was slurried with refluxing ethyl acetate (˜5 mL). Themixture was cooled and a precipitate was isolated by filtration. Thefiltrate was concentrated under reduced pressure. The resulting residuewas slurried twice with ethyl acetate and then combined with theprecipitate to provide 0.8 g of solid. This solid was recrystallizedfrom ethanol (˜5 mL) to provide 0.6 g of1-[(benzyloxy)methyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 168-172°C.

[0714] Analysis: Calculated for C₁₈H₁₆N₄O: % C, 71.0; % H, 5.3; % N,18.4; Found: % C, 70.9; % H, 5,3; % N, 18.4.

Example 114

[0715] 1-(2-{3-[4-(Dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0716] Part A

[0717] Using the general method of Example 12 Part A, N,N-(bistert-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine(2.5 g, 5.36 mmol) was reacted with 4-iodo-N,N-dimethylaniline (1.46 g,5.89 mmol) at 70° C. The reaction was judged complete at 30 minutes. Thesolution was diluted with ethyl acetate, washed with water (3×),saturated aqueous sodium bicarbonate (3×), brine (3×), dried withanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The resulting solid was purified by chromatography over silicagel (98/2 dichloromethane/methanol) to provide 0.883 g of tert-butyl1-[2-({3-[4-(dimethylamino)phenyl]prop-2-ynyl}oxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-ylcarbamateas a brown solid.

[0718] MS(CI) for C₃₃H₃₉N₅O₅ m/z 586 (MH⁺), 486, 386, 229

[0719] Part B

[0720] Using the general method of Example 12 Part B, tert-butyl1-[2-({3-[4-(dimethylamino)phenyl]prop-2-ynyl}oxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-ylcarbamate (0.883 g, 1.507 mmol)was hydrogenated to provide 0.783 g of tert-butyl1-(2-{3-[4-(dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-ylcarbamateas a brown solid.

[0721] MS(CI) for C₃₃H₄₃N₅O₅ m/z 590 (MH⁺), 490, 390, 229

[0722] Part C

[0723] Using the general method of Example 12 Part C, tert-butyl1-(2-{3-[4-(dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-ylcarbamate(0.783 g, 1.327 mmol) was reacted with trifluoroacetic acid (10 mL). Theresulting material was triturated twice with ethyl ether to provide0.634 g of 1-(2-{3-[4-(dimethylamino)phenyl]propoxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine (trifluoroacetate)_(1.5) as awhite solid, m.p. 137-140° C.

[0724] Analysis. Calculated for C₂₃H₂₇N₅O(C₂HF₃O₂)_(1.5): % C, 54.83; %H, 5.22; % N, 12.30. Found: % C, 54.67; % H, 4.91; % N, 12.27

[0725]¹H NMR (300 MHz, DMSO-d₆) δ 9.04-9.11 (bs, 2H), 8.49 (s, 1H), 8.36(d, J=7.3 Hz, 1H), 7.83 (d, J=8.3, 1H), 7.74 (t, J=8.3 Hz, 1H), 7.56 (t,J=6.8 Hz, 1H), 6.71 (d, J=7.8 Hz, 2H), 6.60 (m, 2H), 4.90 (t, J=4.9,2H), 3.83 (t, J=4.9, 2H), 3.27 (t, J=5.9, 2H), 2.28 (s, 6H), 2.25 (t,J=7.8, 2H), 1.54 (p, J=6.4, 6.8, 2H)

[0726] MS(CI) for C₂₃H₂₇N₅O m/z 390 (MH⁺), 229

Example 115

[0727]1-(2-{[(2E)-3-Phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0728] Part A

[0729] A dried round bottom flask was charged with a stir bar, sodiumhydride (60% in mineral oil, 0.19 g, 4.65 mmol) and hexane (2 mL) undernitrogen. By syringe a solution of anhydrous dimethylformamide (10 mL)and 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.902 g, 4.23 mmol) wasadded to the flask and heated to 60° C. for 20 minutes. By syringecinnamyl chloride (0.65 mL, 4.65 mmol) was added to solution. Thereaction was judged complete at 50 minutes with ˜80% conversion todesired product. The volatiles were removed under reduced pressure andthe resulting oil partitioned between dichloromethane and water. Theaqueous layer was extracted with dichloromethane; the organic fractionswere combined, dried with anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting glassy solid waspurified by chromatography over silica gel (95/5dichloromethane/methanol) and dried in vacuum oven at 60° C. for 15hours to provide 0.652 g of1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline asa glassy solid. MS(CI) for C₂₁H₁₉N₃O m/z 330 (MH⁺), 214

[0730] Part B

[0731] Using the general method of Example 1 Part B,1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline(0.652 g, 1.98 mmol) was oxidized to provide 0.67 g of1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline-5N-oxide.The resulting brown solid was used without further purification.

[0732] Part C

[0733] A round bottom flask was charged with a stir bar,1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(0.67 g, 1.98 mmol), dichloromethane (15 mL) and aqueous ammoniumhydroxide (27%, 7 mL) at ambient temperature. p-Toluenesulfonyl chloride(0.415 g, 2.18 mmol) was added in several portions as a solid and theresulting solution stirred. After 20 minutes the reaction was judgedcomplete; the solution was partitioned between aqueous and organic andextracted with dichloromethane (3×). The organic layers were combined,extracted with 5% aqueous sodium bicarbonate (3×), washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The resulting white solid was purified by fivesuccessive recrystalizations from methanol/water to provide 0.086 g of1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white fluffy solid, m.p.183.7-184.3° C.

[0734] Analysis. Calculated for C₂₁H₂₀N₄O: % C, 73.23; % H, 5.85; % N,16.27. Found: % C, 73.11; % H, 5.81; % N, 16.10

[0735]¹H NMR (300 MHz, DMSO-d₆) δ 8.19 (s, 1H), 8.12 (d, J=7.3 Hz, 1H),7.62 (d, J=8.3 Hz, 1H), 7.43 (t, J=8.3 Hz, 1H), 7.19-7.31 (m, 6H), 6.61(s, 2H), 6.33 (d, J=15.6 Hz, 1H), 6.17 (dt, J=16.0, 5.2 Hz, 1H), 4.84(t, J=4.9, 2H), 4.07 (d, J=3.9, 2H), 3.91 (t, J=5.4, 2H)

[0736] MS(CI) for C₂₁H₂₀N₄O m/z 345 (MH⁺), 270, 229

Example 1162-Octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0737]

[0738] Part A

[0739] Using the general method of Example 1 Part A,2-(2-octyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (4.8 g, 14.75 mmol)was reacted with propargyl bromide (80% in toluene, 4.93 mL, 44.25 mmol)to provide 4.84 g of2-octyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as abrown solid.

[0740] Part B

[0741] Using the general method of Example 12 Part A,2-octyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (4.84 g,13.32 mmol) was reacted with iodobenzene (1.7 mL, 14.65 mmol) at 40° C.After 45 minutes the reaction was judged complete. The volatiles wereremoved under reduced pressure and the resulting oil purified bychromatography over silica gel (98/2 (dichloromethane/methanol) toprovide 4.2 g of2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolineas a pale yellow solid.

[0742] MS(CI) for C₂₉H₃₃N₃O m/z 440 (MH⁺), 291

[0743] Part C

[0744] Using the general method of Example 1 Part B,2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline(2.2 g, 5.004 mmol) was oxidized to provide 2.28 g of2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxideas an oil.

[0745] Part D

[0746] Using the general method of Example 115 Part C,2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxide(2.2 g, 4.83 mmol) was aminated. The resulting brown solid was purifiedby trituration with ethyl ether and recrystallization from 2-propanol toprovide 1.23 g of2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a white crystalline solid, m.p. 138-138.7° C.

[0747] Analysis. Calculated for C₂₉H₃₄N₄O: % C, 76.62; % H, 7.54; % N,12.32. Found: % C, 76.6; % H, 7.49; % N, 12.19

[0748]¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.41 (t, J=6.8 Hz, 1H), 7.27-7.36 (m, 3H), 7.18-7.24 (m, 3H),6.45 (s, 2H), 4.78 (t, J=4.9 Hz, 2H), 4.34 (s, 2H), 4.00 (t, J=4.9, 2H),2.94 (t, J=7.8 Hz, 2H), 1.83 (p, J=7.3, 7.3 Hz, 2H), 1.22-1.43 (m, 10H),0.85 (t, J=6.8 Hz, 3H) MS(CI) for C₂₉H₃₄N₄O m/z 455 (MH⁺), 283

Example 1172-Octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0749]

[0750] Part A

[0751] Using the general method of Example 12 Part B,2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline(2.0 g, 4.55 mmol) was hydrogenated to provide 1.78 g of2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline as awhite solid.

[0752]¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.41 (d, J=9.78 Hz, 1H),8.16 (d, J=9.8 Hz, 1H), 7.63-7.71 (m, 2H), 7.06-7.09 (m, 3H), 6.81-6.84(m, 2H), 4.85 (t, J=4.9 Hz, 2 H), 3.84 (t, J=4.9, 2H), 3.25 (t, J=5.9Hz, 2H), 3.04 (t, J=7.8 Hz, 2H), 2.31 (t, J=8.3 Hz, 2H), 1.91 (p, J=7.3,7.3 Hz, 2H), 1.59 (p, J=8.8, 5.8 Hz, 2H), 1.25-1.49 (m, 10H), 0.85 (t,J=7.3 Hz, 3H)

[0753] Part B

[0754] Using the general method of Example 1 Part B,2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline (1.78 g,4.03 mmol) was oxidized to provide 1.8 g of2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxideas an oil.

[0755] Part C

[0756] Using the general method of Example 115 Part C,2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(1.85 g 4.03 mmol) was aminated. The resulting brown solid was purifiedby trituration with ethyl ether and recrystallization from acetonitrileto provide 0.31 g of2-octyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas a white crystalline solid, m.p. 103.8-104.5° C.

[0757] Analysis. Calculated for C₂₉H₃₈N₄O: % C, 75.94; % H, 8.35; % N,12.22. Found: % C, 75.71; % H, 8.46; % N, 12.22

[0758]¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (d, J=7.8 Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.05-7.15 (m,3H), 6.90 (dd, J=5.4, 1.9, 2H), 6.45 (s, 2H), 4.73 (t, J=4.4 Hz, 2H),3.80 (t, J=4.9, 2H), 3.24 (t, J=5.9 Hz, 2H), 2.97 (t, J=7.8 Hz, 2H),2.39 (t, J=7.8 Hz, 2H), 1.85 (p, J=7.3, 7.8 Hz, 2H), 1.62 (p, J=6.8, 6.3Hz, 2H), 1.24-1.44 (m, 10H), 0.84 (t, J=6.8 Hz, 3H) MS(CI) for C₂₉H₃₈N₄Om/z 459 (MH⁺), 373, 285

Example 1182-Methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0759]

[0760] Part A

[0761] Using the general method of Example 1 Part A,2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (4.0 g, 17.6 mmol)was reacted with propargyl bromide (80% in toluene, 5.9 mL, 52.8 mmol)to provide 3.6 g of2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as adark brown oil. MS(CI) for C₁₆H₁₅N₃O m/z 266 (MH⁺), 184

[0762] Part B

[0763] Using the general method of Example 12 Part A,2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (3.6 g,13.57 mmol) was reacted with iodobenzene (1.7 mL, 14.92 mmol) at ambienttemperature. After 20 hours the reaction was judged complete. Thesolution was basified with 5% aqueous sodium bicarbonate and thenextracted with dichloromethane (3×). The organics were combined, washedwith water (3×), washed with brine, dried with anhydrous sodium sulfate,filtered and then concentrated under reduced pressure. Purification wascompleted by chromatography over silica gel (95/5dichloromethane/methanol) and recrystallization from acetonitrile toprovide 1.94 g of2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolineas a light yellow solid.

[0764] MS(CI) for C₂₂H₁₉N₃O m/z 342 (MH⁺), 228

[0765] Part C

[0766] Using the general method of Example 1 Part B,2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline(1.0 g, 2.93 mmol) was oxidized to provide 1.3 g of2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxideas a tan solid.

[0767]¹H NMR (300 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.78 (d, J=8.3 Hz, 1H),8.48 (d, J=7.8 Hz, 1H), 7.79 (m, 2H), 7.26-7.35 (m, 3H), 7.09-7.18 (m,2H), 4.86 (t, J=5.4 Hz, 2H), 4.34 (s, 2H), 4.04 (t, J=4.9, 2H), 2.66 (s,3H)

[0768] Part D

[0769] Using the general method of Example 115 Part C,2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxide(1.05 g, 2.93 mmol) was aminated. The resulting tan solid was purifiedby trituration with ethyl ether, recrystalization from toluene,chromatography over silica gel (98/2 dichloromethane/methanol) toprovide 0.261 g of2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a white powder, m.p. 142.7-143.3° C.

[0770] Analysis. Calculated for C₂₂H₂₀N₄O: % C, 74.14; % H, 5.66; % N,15.72. Found: % C, 73.97; % H, 5.77; % N, 15.77

[0771]¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, J=8.3 Hz, 1H), 7.61 (d, J=8.3Hz, 1H), 7.41 (t, J=8.3 Hz, 1H), 7.28-7.35 (m, 3H), 7.12-7.24 (m, 3H),6.52 (s, 2H), 4.77 (t, J=4.9 Hz, 2H), 4.36 (s, 2H), 4.02 (t, J=4.9, 2H),2.62 (s, 3H) MS(CI) for C₂₂H₂₀N₄O m/z 357 (MH⁺), 243, 199

Example 1192-Methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0772]

[0773] Part A

[0774] Using the general method of Example 12 Part B,2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline(0.9 g, 2.636 mmol) was hydrogenated to provide 0.845 g of2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline as awhite solid.

[0775]¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.44 (d, J=7.3 Hz, 1H),8.16 (d, J=7.8 Hz, 1H), 7.65-7.70 (m, 2H), 7.04-7.08 (m, 3H), 6.79-6.83(m, 2H), 4.85 (t, J=4.9 Hz, 2H), 3.85 (t, J=5.4 Hz, 2H), 3.23 (t, J=6.4,2H), 2.70 (s, 3H), 2.3 (t, J=7.8 Hz, 2H), 1.58 (p, J=6.36, 6.36 Hz, 2H)

[0776] Part B

[0777] Using the general method of Example 1 Part B,2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline (0.845g, 2.45 mmol) was oxidized to provide 0.88 g of2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxideas a glassy solid. Material was used without further purification.

[0778] Part C

[0779] Using the general method of Example 115 Part C,2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(0.88 g, 2.45 mmol) was aminated. The resulting brown solid was purifiedby trituration with ethyl ether and recrystallized from toluene toprovide 0.596 g of2-methyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas a white powder, m.p. 129.7-130.7° C.

[0780] Analysis. Calculated for C₂₂H₂₄N₄O: % C, 73.31; % H, 6.71; % N,15.54. Found: % C, 73.21; % H, 6.66; % N, 15.58

[0781]¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (d, J=8.3 Hz, 1H), 7.62 (d, J=7.3Hz, 1H), 7.41 (t, J=7.3 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 7.05-7.14 (m,3H), 6.88 (dd, J=6.8, 2.4 Hz, 2H), 6.52 (s, 2H), 4.73 (t, J=4.9 Hz, 2H),3.80 (t, J=4.9, 2H), 3.24 (t, J=6.4 Hz, 2H), 2.64 (s, 3H), 2.38 (t,J=8.3 Hz, 2H), 1.62 (p, J=6.8, 6.4 Hz, 2H)

[0782] MS(CI) for C₂₂H₂₄N₄O m/z 361 (MH⁺), 347, 199

Example 1202-(Methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0783]

[0784] Part A

[0785] Using the general method of Example 1 Part2-[2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (2.53 g, 9.33mmol) was reacted with propargyl bromide (80% in toluene, 3.11 mL, 27.9mmol) to provide 2.72 g of2-(methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinolineas an oil. MS(CI) for C₁₈H₁₉N₃O₂ m/z 310 (MH⁺), 278, 196

[0786] Part B

[0787] Using the general method of Example 12 Part A,2-(methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline(2.72 g, 1.79 mmol) was reacted with iodobenzene (1.1 mL, 9.67 mmol) atambient temperature. After 45 minutes the reaction was judged complete.The volatiles were removed under reduced pressure and the resulting oilpartitioned between dichloromethane and 5% aqueous sodium bicarbonate.The aqueous layer was extracted with dichloromethane. The organicfractions were combined, washed with brine, dried with anhydrous sodiumsulfate, and then concentrated under reduced pressure to leave a brownsolid. The solid was purified by chromatography over silica gel (95/5(dichloromethane/methanol) and trituration with hexane to provide 2.39 gof2-(methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolineas a yellow solid. MS(CI) for C₂₄H₂₃N₃O₂ m/z 386 (MH⁺), 354, 270

[0788] Part C

[0789] Using the general method of Example 1 Part B,2-(methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline(1.19 g, 3.097 mmol) was oxidized to provide 1.24 g of2-(methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxideas an glassy solid.

[0790] Part D

[0791] Using the general method of Example 115 Part C,2-(methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxide(1.243 g, 3.097 mmol) was aminated. The resulting brown oil was purifiedby chromatography over silica gel (98/2 dichloromethane/methanol),recrystallization from ethyl acetate and acetonitrile to provide 0.379 gof2-(methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 134.5-135.5° C.

[0792] Analysis. Calculated for C₂₄H₂₄N₄O₂: % C, 71.98; % H, 6.04; % N,13.99. Found: % C, 72.21; % H, 5.98; % N, 14.29

[0793]¹H NMR (300 MHz, DMSO-d₆) δ 8.09 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.41 (t, J=8.3 Hz, 1H), 7.28-7.36 (m, 3H), 7.18-7.24 (m, 3H),6.50 (s, 2H), 4.82 (t, J=4.9 Hz, 2H), 4.36 (s, 2H), 4.01 (t, J=4.9, 2H),3.84 (t, J=6.8 Hz, 2H), 3.29 (s, 3H), 3.23 (t, J=6.8 Hz, 2H)

[0794] MS(CI) for C₂₄H₂₄N₄O₂ m/z 401 (MH⁺), 255, 183

Example 1212-(2-Methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0795]

[0796] Part A

[0797] Using the general method of Example 12 Part B,2-(2-methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline(1.2 g, 3.11 mmol), was hydrogenated to provide 1.01 g of2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolineas an oil.

[0798] MS(CI) for C₂₄H₂₇N₃O₂ m/z 390 (MH⁺), 235

[0799] Part B

[0800] Using the general method of Example 1 Part B,2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline(1.01 g, 2.60 mmol) was oxidized to provide 1.05 g of2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxideas an brown oil.

[0801] Part C

[0802] Using the general method of Example 115 Part C,2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(1.05 g, 2.601 mmol) was aminated. The resulting brown solid waspurified by chromatography over silica gel (98/2dichloromethane/methanol), recrystallization from ethyl acetate/hexaneto provide 0.111 g of2-(2-methoxyethyl)-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 103.8-104.5° C.

[0803] Analysis. Calculated for C₂₄H₂₈N₄O₂ (H₂O)_(0.2): % C, 70.63; % H,7.01; % N, 13.73. Found: % C, 70.38; % H, 6.80; % N, 13.57

[0804]¹H NMR (300 MHz, DMSO-d₆) δ 8.09 (d, J=7.3 Hz, 1H), 7.63 (d, J=8.3Hz, 1H), 7.42 (t, J=6.8 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.08-7.15 (m,3H), 6.89 (d, J=5.4 Hz, 2H), 6.49 (s, 2H), 4.78 (t, J=4.9 Hz, 2H), 3.86(t, J=6.8, 2H), 3.80 (t, J=5.4 Hz, 2H), 3.30 (s, 3H), 3.22-3.28 (m, 4H),2.39 (t, J=8.3 Hz, 2H), 1.62 (p, J=8.3, 6.4 Hz, 2H)

[0805] MS(CI) for C₂₄H₂₈N₄O₂ m/z 405 (MH⁺), 373, 235

Example 1222-(Ethoxymethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0806]

[0807] Part A

[0808] Using the general method of Example 1 Part A2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (1.39 g,5.123 mmol) was reacted with propargyl bromide (80% in toluene, 1.7 mL,15.37 mmol) to provide 1.6 g of2-(ethoxymethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinolineas an oil. MS (CI) for C₁₈H₁₉N₃O₂ m/z 310 (MH⁺), 371, 270

[0809] Part B

[0810] Using the general method of Example 12 Part A,2-(ethoxymethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline(1.5 g, 4.13 mmol) was reacted with iodobenzene (0.51 mL, 4.54 mmol) at40° C. After 50 minutes the reaction was judged complete. The volatileswere removed under reduced pressure and the resulting oil waspartitioned between dichloromethane and 5% aqueous sodium bicarbonate.The aqueous layer was extracted with dichloromethane. The organicfractions were combined, washed with brine, dried with anhydrous sodiumsulfate, and then concentrated under reduced pressure to leave a brownoil. The oil was purified by chromatography over silica gel (98/2dichloromethane/methanol) to provide 1.25 g of2-(ethoxymethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolineas a brown glassy solid. MS (CI) for C₂₄H₂₃N₃O₂ m/z 386 (MH⁺), 342, 272

[0811] Part C

[0812] Using the general method of Example 1 Part B,2-(ethoxymethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline(0.655 g, 1.70 mmol) was oxidized to provide 0.68 g of2-(ethoxymethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxide as an oil.

[0813] Part D

[0814] Using the general method of Example 115 PartC2-(ethoxymethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxide(0.682 g, 1.700 mmol) was aminated. The resulting brown solid waspurified by chromatography over silica gel (98/2dichloromethane/methanol) to provide 0.297 g of2-(ethoxymethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a white granular solid, m.p. 110.8-111.7° C.

[0815] Analysis. Calculated for C₂₄H₂₄N₄O₂ (H₂O)_(0.1): % C, 71.66; % H,6.06; % N, 13.93. Found: % C, 71.56; % H, 5.96; % N, 13.74

[0816]¹H NMR (300 MHz, DMSO-d₆) δ 8.13 (d, J=7.8 Hz, 1H), 7.63 (d, J=8.3Hz, 1H), 7.44 (t, J=6.8 Hz, 1H), 7.28-7.36 (m, 3H), 7.19-7.26 (m, 3H),6.67 (s, 2H), 4.88 (t, J=5.4 Hz, 2H), 4.81 (s, 2H), 4.38 (s, 2H), 4.03(t, J=5.9, 2H), 3.55 (q, J=6.8, 7.3 Hz, 2H), 1.15 (t, J=6.8 Hz, 3H)

[0817] MS(CI) for C₂₄H₂₄N₄O₂ m/z 401 (MH⁺), 371, 285

Example 1232-Butyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine

[0818]

[0819] Part A

[0820] Using the general method of Example 1 Part A,2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (5.0 g, 18.56 mmol)was reacted with propargyl bromide (80% in toluene, 6.3 mL, 55.62 mmol)to provide 4.02 g of2-butyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as a tansolid.

[0821] MS(CI) for C₁₉H₂₁N₃O m/z 308 (MH⁺), 268, 220

[0822] Part B

[0823] Using the general method of Example 12 Part A,2-butyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (4.0 g,13.08 mmol) was reacted with iodobenzene (1.6 mL, 14.38 mmol) at 90° C.After 15 minutes the reaction was judged complete. The volatiles wereremoved under reduced pressure and the resulting oil was purified bychromatography over silica gel (98/2 dichloromethane/methanol) andrecrystallization from mixture of ethyl acetate/hexane to provide 3.1 gof2-butyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolineas a tan solid.

[0824] Part C

[0825] Using the general method of Example 1 Part B,2-butyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline(1.0 g, 2.61 mmol) was oxidized to provide 1.0 g of2-butyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxideas an oil.

[0826] Part D

[0827] Using the general method of Example 115 Part C,2-butyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline-5N-oxide(1.04 g, 2.60 mmol) was aminated. The resulting brown solid was purifiedby trituration with ethyl ether, two times with chromatography oversilica gel (8/2 dichloromethane/ethyl acetate, 98/2dichloromethane/methanol) to provide 0.450 g of2-butyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amineas a white powder, m.p. 133-140° C.

[0828] Analysis. Calculated for C₂₅H₂₆N₄O(H₂O)_(0.2): % C, 74.67; % H,6.62; % N, 13.93. Found: % C, 74.65; % H, 6.60; % N, 14.00

[0829]¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.3Hz, 1H), 7.41 (t, J=7.3 Hz, 1H), 7.29-7.36 (m, 3H), 7.17-7.24 (m, 3H),6.45 (s, 2H), 4.78 (t, J=4.9 Hz, 2H), 4.34 (s, 2H), 4.01 (t, J=4.9, 2H),2.95 (t, J=8.3 Hz, 2H), 1.81 (p, J=7.3, 8.3 Hz, 2H), 1.44 (sextet,J=7.3, 7.3, 7.8 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H)

[0830] MS(CI) for C₂₅H₂₆N₄O m/z 399 (MH⁺), 283, 267

Example 1242-Butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0831]

[0832] Part A

[0833] Using the general method of Example 12 Part B,2-butyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline(2.4 g, 6.26 mmol) was hydrogenated to provide 1.67 g of2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline as awhite solid.

[0834] MS(CI) for C₂₅H₂₉N₃O m/z 388 (MH⁺), 279

[0835] Part B

[0836] Using the general method of Example 1 Part B,2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline (1.68 g,4.34 mmol) was oxidized to provide 1.75 g of2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxideas glassy solid.

[0837] MS(CI) for C₂₅H₂₉N₃O₂ m/z 404 (MH⁺), 388

[0838] Part C

[0839] Using the general method of Example 115 Part C,2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(1.75 g, 4.34 mmol) was aminated. The resulting tan solid was purifiedby recrystallization from acetonitrile to provide 0.572 g of2-butyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas tan crystalline solid, m.p. 80.8-81.3° C.

[0840] Analysis. Calculated for C₂₅H₃₀N₄O(H₂O)_(0.3): % C, 73.61; % H,7.56; % N, 13.73. Found: % C, 73.3; % H, 7.65; % N, 13.67

[0841]¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.41 (t, J=7.3 Hz, 1H), 7.21 (t, J=7.3 Hz, 1H), 7.05-7.14 (m,3H), 6.89 (d, J=7.3 Hz, 2H), 6.45 (s, 2H), 4.74 (t, J=4.4 Hz, 2H), 3.80(t, J=4.9, 2H), 3.24 (t, J=5.9 Hz, 2H), 2.98 (t, J=7.8 Hz, 2H), 2.39 (t,J=7.8 Hz, 2H), 1.84 (p, J=7.3, 8.3 Hz, 2H), 1.62 (p, J=7.8, 5.9 Hz, 2H),1.48 (sextet, J=7.3, 7.3, 7.8 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H)

[0842] MS(CI) for C₂₅H₃₀N₄O m/z 403 (MH⁺), 213

Example 1251-[2-(Benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0843]

[0844] Part A

[0845] Using the general method of Example 1 Part B,1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline(0.324 g, 0.897 mmol) was oxidized to provide 0.338 g of1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-5N-oxideas a brown oil.

[0846] Part B

[0847] Using the general method of example 115 Part C,1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(0.339 g, 0.897 mmol) was aminated. The resulting tan solid was purifiedby recrystallized from acetonitrile to provide 0.187 g of1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a white powder, m.p. 144.5-146.0° C.

[0848] Analysis. Calculated for C₂₂H₂₄N₄O₂: % C, 70.19; % H, 6.43; % N,14.88. Found: % C, 69.96; % H, 6.29; % N, 15.09

[0849]¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.3Hz, 1H), 7.43 (t, J=6.8 Hz, 1H), 7.19-7.24 (m, 4H), 7.11-7.14 (m, 2H),6.6 (s, 2H), 4.87 (t, J=5.4, 2H), 4.79 (s, 2H), 4.44 (s, 2H), 3.90 (t,J=5.4, 2H), 3.52 (q, J=6.8, 6.8 Hz, 2H), 1.13 (t, J=6.8 Hz, 3H)

[0850] MS(CI) for C₂₂H₂₄N₄O₂ m/z 377 (MH⁺), 331, 241

Example 1261-[2-(Benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine

[0851]

[0852] Part A

[0853] Using the general method of Example 1 Part B,1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinoline (2.3 g, 6.39mmol) was oxidized to provide 2.4 g of1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinoline-5N-oxide as abrown oil.

[0854] MS(CI) for C₂₃H₂₅N₃O₂ m/z 376 (MH⁺), 360, 270

[0855] Part B

[0856] Using the general method of example 1 Part C,1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinoline-5N-oxide (2.4g, 6.39 mmol) was reacted with trichloroacetyl isocyanate (1.45 g, 7.678mmol) to provide 3.3 g ofN-{1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-yl}-2,2,2-trichloroacetamideas a brown oil.

[0857] Part C

[0858] Using the general method of example 1 Part D,N-{1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-yl}-2,2,2-trichloroacetamide(3.3 g, 6.39 mmol) was hydrolyzed with sodium methoxide (5 mL of 25% inmethanol). The resulting tan solid was purified by chromatography oversilica gel (98/2 dichloromethane/methanol), recrystallized from methanoland dried under vacuum at 60° C. for 18 hours to provide 0.174 g of1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine as awhite solid, m.p. 133-135° C.

[0859] Analysis. Calculated for C₂₃H₂₆N₄O: % C, 73.77; % H, 7.00; % N,14.96. Found: % C, 73.51; % H, 7.06; % N, 14.92

[0860]¹H NMR (300 MHz, DMSO-d₆) δ 8.03 (d, J=7.3 Hz, 1H), 7.60 (d, J=8.3Hz, 1H), 7.39 (t, J=6.8 Hz, 1H), 7.17-7.24 (m, 4H), 7.10-7.12 (m, 2H),6.45 (s, 2H), 4.76 (t, J=5.4, 2H), 4.41 (s, 2H), 3.89 (t, J=4.9, 2H),2.94 (t, J=8.3 Hz, 2H), 1.77 (p, J=7.8, 7.8 Hz, 2H), 1.40 (sextet,J=7.8, 7.3, 6.8 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H)

[0861] MS(CI) for C₂₃H₂₆N₄O m/z 375 (MH⁺), 242, 183

Example 1271-[2-(Benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine

[0862]

[0863] Part A

[0864] Using the general method of Example 1 Part B,1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinoline (6 g, 18.9mmol) was oxidized to provide 6.3 g of1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinoline-5N-oxide as abrown solid.

[0865] Part B

[0866] Using the general method of example 1 Part C,1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinoline-5N-oxide (6.3g, 18.9 mmol) was reacted with trichloroacetyl isocyanate (4.95 g, 26.27mmol) to provide 10.4 g ofN-{1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-yl}-2,2,2-trichloroacetamideas a brown solid.

[0867] Part C

[0868] Using the general method of example 1 Part D,N-{1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-yl}-2,2,2-trichloroacetamide(10.46 g, 21.89 mmol) was hydrolyzed with sodium methoxide (20 mL of 25%in methanol). The resulting brown solid was purified by chromatographyover silica gel (98/2 dichloromethane/methanol) and dried under vacuumat 60° C. for 18 hours to provide 1.036 g of1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as awhite solid, m.p. 159-160° C.

[0869] Analysis. Calculated for C₂₀H₂₀N₄O: % C, 72.27; % H, 6.06; % N,16.85. Found: % C, 72.17; % H, 5.96; % N, 16.81

[0870]¹H NMR (300 MHz, DMSO-d₆) δ 8.04 (d, J=7.3 Hz, 1H), 7.59 (d, J=8.3Hz, 1H), 7.39 (t, J=8.3 Hz, 1H), 7.15-7.27 (m, 4H), 7.08-7.13 (m, 2H),6.49 (s, 2H), 4.75 (t, J=5.4, 2H), 4.43 (s, 2H), 3.90 (t, J=5.4, 2H),2.61 (s, 3H)

[0871] MS(CI) for C₂₀H₂₀N₄O m/z 333 (MH⁺), 243, 199

Example 1281-[2-(Benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-c]quinolin-4-amine

[0872]

[0873] Part A

[0874] Using the general method of Example 1 Part B,1-[2-(benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-c]quinoline (2.4 g, 5.8mmol) was oxidized to provide 2.5 g of1-[2-(benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-c]quinoline-5N-oxide as abrown oil.

[0875] Part B

[0876] Using the general method of example 115 Part C,1-[2-(benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-c]quinoline-5N-oxide (2.50g, 5.80 mmol) was aminated. The resulting oil was purified bychromatography over silica gel (98/2 dichloromethane/methanol) andrecrystallized from acetonitrile to provide 0.75 g1-[2-(benzyloxy)ethyl]-2-octyl-1H-imidazo[4,5-c]quinolin-4-amine as awhite powder, m.p. 110-111° C. Analysis. Calculated for C₂₇H₃₄N₄O: % C,75.31; % H, 7.96; % N, 13.01. Found: % C, 75.20; % H, 7.88; % N, 13.00

[0877]¹H NMR (300 MHz, DMSO-d₆) δ 8.03 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.3Hz, 1H), 7.40 (t, J=7.3 Hz, 1H), 7.17-7.26 (m, 4H), 7.10-7.13 (m, 2H),6.45 (s, 2H), 4.76 (t, J=4.9, 2H), 4.41 (s, 2H), 3.88 (t, J=4.9, 2H),2.93 (t, J=7.8 Hz, 2H), 1.79 (p, J 7.3, 7.3 Hz, 2H), 1.20-1.38 (m, 10H),0.85 (t, J=6.3 Hz, 3H)

[0878] MS(CI) for C₂₇H₃₄N₄O m/z 431 (MH⁺), 291, 214

Example 129

[0879]2-(2-Methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0880] Part A

[0881] Under anitrogen atmosphere, 2-phenoxyethylamine (17.6 ml, 0.13mol) was added dropwise to a chilled (ice bath) solution of4-chloro-3-nitroquinoline (21.5 g, 0.1 mol), triethylamine (21.5 ml,0.16 mol) in dichloromethane (500 ml). The reaction was maintained atambient temperature overnight. Water was added and the phases wereseparated. The organic phase was dried (MgSO₄), filtered, and the bulkof the solvent was removed under vacuum. Hexane was added and thesolution was chilled in a refrigerator. The resulting precipitate wasrecovered by vacuum filtration to provide 19.1 g of3-nitro-N-(2-phenoxyethyl)quinolin-4-amine as a yellow solid.

[0882] Part B

[0883] 3-Nitro-N-(2-phenoxyethyl)quinolin-4-amine (6.0 g, 19 mmol), 5%platinum on carbon (1.5 g) and ethyl acetate (300 ml) were placed in ahydrogenation flask. The mixture was shaken overnight under a hydrogenpressure of 40 psi (2.8 Kg/cm²). The reaction mixture was filtered andthe catalyst was washed with ethyl acetate. The filtrate was dried(MgSO₄), filtered, and concentrated under vacuum to near dryness. Hexanewas added and the resulting precipitate was collected by vacuumfiltration to provide 4.9 g of N4-(2-phenoxyethyl)quinoline-3,4-diamineas a pale yellow solid.

[0884] Part C

[0885] 3-methoxypropanoyl chloride (0.86 ml, 7.9 mmol) was addeddropwise over a 30 minute period to a chilled (ice bath) solution ofN⁴-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol) indichloromethane (100 ml). After a few hours, a precipitate formed. Thesolvent volume was reduced under vacuum to near dryness and hexane (100ml) was added. Vacuum filtration provided 2.9 g of3-methoxy-N-{4-[(2-phenoxyethyl)amino]quinolin-3-yl}propanamide as ahydrochloride salt.

[0886] Part D

[0887] The product from Part C (2.9 g) and a 7.5% solution of ammonia inmethanol (200 ml) were placed in a pressure vessel. The vessel wassealed and then heated at 160° C. for 6 hours. After the mixture wascooled to ambient temperature, it was concentrated under vacuum. Theresidue was partitioned between dichloromethane (150 ml) and water (150ml). The fractions were separated and the aqueous fraction was extractedwith dichloromethane (100 ml). The organic fractions were combined,dried (MgSO₄), and filtered. The bulk of the solvent was removed undervacuum and hexane was added to yield a white precipitate. Vacuumfiltration provided 1.8 g of2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline as awhite solid.

[0888] Part E

[0889] 3-Chloroperoxybenzoic acid (1.5 g, 8.7 mmol, 60% by weight) wasadded in three portions over a period of 20 minutes to2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline (1.8 g,5.2 mmol) in chloroform (100 ml). The reaction mixture was maintained atambient temperature overnight and then washed with saturated sodiumbicarbonate followed by water. The organic fraction was dried (MgSO₄)and concentrated under vacuum to near dryness. Hexane was added and theresulting precipitate was recovered by vacuum filtration to yield 1.6 gof2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline-5N-oxideas a light yellow powder.

[0890] Part F

[0891] Under a nitrogen atmosphere, trichloroacetyl isocyanate (0.8 ml,6.6 mmol) was added dropwise to a solution of2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(1.6 g, 4.4 mmol) in dichloromethane (100 ml) and the reaction wasmaintained at ambient temperature for 2 hours. Ammonium hydroxide (5drops, 7% by weight in methanol) was added and the reaction wasmaintained at ambient temperature for an additional 2.5 days. Sodiumhydroxide (10%) was added and the two phases were separated. The organicphase was concentrated and purified by flash column chromatography(silica gel, 9:1 dichloromethane/methanol). Fractions containing productwere combined, concentrated in vacuo, dissolved in boiling toluene, andtreated with activated charcoal. The mixture was filtered to remove thecharcoal and the filtrate was cooled. The resulting precipitate wasrecovered by filtration and dried in a vacuum oven (80° C.) to provide0.68 g of2-(2-methoxyethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a tan powder, m.p. 171.0-174.0° C.

[0892]¹H NMR (300 MHz, DMSO-d₆) δ 8.19 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.3Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.29-7.20 (m, 3H), 6.90 (t, J=7.4 Hz,1H), 6.82 (d, J=8.2 Hz, 2H), 6.58 (s, 2H), 5.01 (t, J=5.0 Hz, 2H), 4.43(t, J=5.0 Hz, 2H), 3.87 (t, J=6.9 Hz, 2H), 3.34 (s, 3H), 3.30 (t, J=6.9Hz, 2H);

[0893] MS(CI) m/e 363.1820 (363.1821 calcd for C₂₁H₂₃N₄O₂, M+H);

[0894] Anal calcd for C₂₁H₂₂N₄O₂: C, 69.59; H, 6.12; N, 15.46. Found: C,69.32; H, 6.17; N, 15.48.

Example 130

[0895] 2-Isobutyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0896] N⁴-(2-Phenoxyethyl)quinoline-3,4-diamine (1.5 g, 5.4 mmol) andisovaleryl chloride (0.8 ml, 6.4 mmol) were combined and treatedaccording to the general procedures of Parts C-E of Example 129. Theresulting product,2-isobutyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline-5N-oxide (1.6g, 4.5 mmol) was dissolved in dichloromethane (200 ml) and ammoniumhydroxide (50 ml) was added. The reaction was chilled (ice bath) andp-toluenesulfonyl chloride (0.85 g, 4.5 mmol) was slowly added over aperiod of 20 minutes. The cooling bath was removed and the reaction wasmaintained at ambient temperature overnight. The phases were separatedand the organic phase was sequentially washed with 1% aqueous sodiumcarbonate (3×), water, brine; dried (Na₂SO₄); and concentrated to neardryness in vacuo. Hexane was added to provide a precipitate. The solidwas collected and purified by recrystallization from acetonitrile toyield 0.96 g of2-isobutyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tanpowder, m.p. 176.6-177.8° C.

[0897]¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.3Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.28-7.20 (m, 3H), 6.89 (t, J=7.3 Hz,1H), 6.81 (d, J=8.6 Hz, 2H), 6.49 (s, 2H), 4.98 (t, J=4.8 Hz, 2H), 4.42(t, J=4.8 Hz, 2H), 2.89 (d, J=7.2 Hz, 2H), 2.40-2.22 (m, 1H), 1.02 (d,J=6.6 Hz, 6H);

[0898]¹³C NMR (75 MHz, DMSO-d₆) 158.6, 153.9, 152.4, 145.5, 132.9,130.1, 127.1, 126.9, 121.5, 120.8, 115.3, 114.7, 66.6, 44.4, 35.3, 27.1,22.4;

[0899] MS(CI) m/e 361.2017 (361.2028 calcd for C₂₂H₂₅N₄O, M+H);

[0900] Anal calcd for C₂₂H₂₄N₄O: C, 73.31; H, 6.71; N, 15.54. Found: C,73.33; H, 6.56; N, 15.79.

Example 1312-Isopropyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0901]

[0902] N⁴-(2-Phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol) andisobutyryl chloride (0.9 ml, 8.6 mmol) were combined and treatedaccording to the general procedure described in Example 130.Recrystallization from acetonitrile provided 0.82 g of2-isopropyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as atan solid, m.p. 229-231° C.

[0903]¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d, J=7.5 Hz, 1H), 7.65-7.62 (dd,J=8.3, 1.1 Hz, 1H), 7.46-4.40 (dt, J=8.2, 1.1 Hz, 1H), 7.29-7.20 (m,3H), 6.90 (t, J=7.3 Hz, 1H), 6.81 (d, J=7.8 Hz, 2H), 6.46 (s, 2H), 5.01(t, J=4.9 Hz, 2H), 4.42 (t, J=4.9 Hz, 2H), 3.54 (septet, J=6.8 Hz, 1H),1.41 (d, J=6.8 Hz, 6H);

[0904]¹³C NMR (75 MHz, DMSO-d₆) 159.3, 158.5, 152.3, 145.4, 132.6,130.1, 126.84, 126.78, 121.5, 120.7, 115.3, 114.6, 66.5, 44.1, 25.2,21.8;

[0905] MS(CI) m/e 347.1872 (347.1872 calcd for C₂₁H₂₃N₄O, M+H);

[0906] Anal calcd for C₂₁H₂₂N₄O: C, 72.81; H, 6.40; N, 16.17. Found: C,72.48; H, 6.59; N, 16.50.

Example 132 2-Butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0907]

[0908] N⁴-(2-Phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol),xylenes (150 ml), and trimethylorthovalerate (2.5 ml, 14.3 mmol) werecombined under an atmosphere of nitrogen and heated at refluxtemperature for 4 days. The external heat was increased andapproximately 35 ml of xylenes was removed by distillation. The reactionwas slowly cooled to room temperature and a precipitate formed. Thesolid was recovered by vacuum filtration to yield 2.4 g of2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline as a light tancrystalline solid.

[0909] 2-Butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline was treatedaccording to the general procedures described in Parts E and F ofExample 129. A final recrystallization from acetonitrile provided 0.93 gof 2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as whiteneedles, m.p. 168.3-169.5° C.

[0910]¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=8.1 Hz, 1H), 7.63 (d, J=8.3Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.28-7.20 (m, 3H), 6.90 (t, J=7.4 Hz,1H), 6.82 (d, J=8.5 Hz, 2H), 6.47 (s, 2H), 4.97 (t, J=4.8 Hz, 2H), 4.43(t, J=4.8 Hz, 2H), 3.00 (t, J=7.7 Hz, 2H), 1.86 (m, 2H), 1.47 (m, 2H),0.96 (t, J=7.3 Hz, 3H);

[0911]¹³C NMR (75 MHz, DMSO-d₆) 158.5, 154.6, 152.3, 145.6, 132.9,130.1, 126.8, 121.5, 120.7, 115.2, 114.6, 66.7, 44.4, 29.3, 26.2, 21.9,13.6;

[0912] MS(CI) m/e 361.2032 (361.2028 calcd for C₂₂H₂₅N₄O, M+H);

[0913] Anal calcd for C₂₂H₂₄N₄O: C, 73.31; H, 6.71; N, 15.54. Found: C,73.15; H, 6.69; N, 15.57.

Example 1331-(2-Phenoxyethyl)-2-(phenoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0914]

[0915] According to the general procedure described in Part C of Example129, phenoxyacetyl chloride (1.2 ml, 8.6 mmol) was reacted withN⁴-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol). The productof this reaction was treated according to the general proceduresdescribed in Parts D-F of Example 129. Recrystallization fromacetonitrile provided 0.65 g of the final product,1-(2-phenoxyethyl)-2-(phenoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,as a tan powder, m.p. 168.5-170.0° C.

[0916]¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (d, J=7.9 Hz, 1H), 7.64 (dd,J=8.3, 1.0 Hz, 1H), 7.47 (m, 1H), 7.38-7.14 (m, 7H), 7.01 (t, J=7.3 Hz,1H), 6.89 (t, J=7.3 Hz, 1H), 6.81 (d, J=7.8 Hz, 2H), 6.69 (s, 2H), 5.53(s, 2H), 5.29 (t, J=5.0 Hz, 2H), 4.48 (t, J=5.0 Hz, 2H);

[0917]¹³C NMR (75 MHz, DMSO-d₆) 158.5, 152.7, 149.2, 146.1, 134.1,130.2, 130.1, 127.6, 127.0, 126.9, 122.0, 121.6, 121.5, 121.4, 115.3,115.1, 114.7, 66.6, 62.7, 45.0;

[0918] MS(CI) m/e 411.1813 (411.1821calcd for C₂₅H₂₃N₄O₂, M+H);

[0919] Anal calcd for C₂₅H₂₂N₄O₂: C, 73.15; H, 5.40; N, 13.65. Found: C,73.36; H, 5.30; N, 13.66.

Example 134

[0920]2-(4-Methoxybenzyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0921] According to the general procedure described in Part C of Example129, 4-methoxyphenylacetyl chloride (1.2 ml, 7.9 mmol) was reacted withN⁴-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol). The productof this reaction was treated according to the general proceduresdescribed in Parts D-F of Example 129. Recrystallization fromacetonitrile provided 1.1 g of the final product,2-(4-methoxybenzyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine,as a tan solid, m.p. 201.0-203.6° C.

[0922]¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (d, J=8.1 Hz, 1H), 7.63 (d, J=8.3Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.26-7.18 (m, 5H), 6.93-6.87 (m, 3H),6.74 (d, J=8.2 Hz, 2H), 6.58 (s, 2H), 4.89 (t, J=5.1 Hz, 2H), 4.40 (s,2H), 4.24 (t, J=5.1 Hz, 2H), 3.70 (s, 3H);

[0923] MS(CI) m/e 425.1948 (425.1978 calcd for C₂₆H₂₅N₄O₂, M+H);

[0924] Anal calcd for C₂₆H₂₄N₄O₂: C, 73.57; H, 5.70; N, 13.20. Found: C,73.25; H, 5.93; N, 13.06.

Example 135

[0925]2-Cyclopentyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0926] N⁴-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol) andcyclopentanecarbonyl chloride (1.1 ml, 8.6 mmol) were combined andtreated according to the general procedure described in Example 130.Recrystallization from acetonitrile provided 1.4 g of2-cyclopentyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as atan solid, m.p. 216.0-217.9° C.

[0927]¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d, J=8.1 Hz, 1H), 7.63 (d, J=8.2Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.28-7.20 (m, 3H), 6.90 (t, J=7.3 Hz,1H), 6.81 (d, J=8.5 Hz, 2H), 6.46 (s, 2H), 5.02 (t, J=4.9 Hz, 2H), 4.42(t, J=4.9 Hz, 2H), 3.60 (pentet, J=8.2 Hz, 1H), 2.18-1.67 (m, 8H);

[0928]¹³C NMR (75 MHz, DMSO-d₆) 158.5, 158.3, 152.9, 144.6, 133.0,130.1, 126.8, 121.5, 120.8, 115.3, 114.7, 66.5, 44.2, 36.1, 32.3, 25.3;

[0929] MS(CI) m/e 373.2030 (373.2028 calcd for C₂₃H₂₅N₄O, M+H);

[0930] Anal calcd for C₂₃H₂₄N₄O: C, 74.17; H, 6.49; N, 15.04. Found: C,74.18; H, 6.59; N, 15.08.

Example 136

[0931]2-[(2-Methoxyethoxy)methyl]-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0932] N⁴-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol) and2-(2-methoxyethoxy)acetyl chloride (1.3 g, 8.6 mmol) were combined andtreated according to the general procedure described in Example 130.Recrystallization from methanol provided 1.6 g of2-[(2-methoxyethoxy)methyl]-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amineas white needles, m.p. 170.0-171.5° C.

[0933]¹H NMR (300 MHz, CDCl₃) δ 8.06 (dd, J=8.3, 1.0 Hz, 1H), 7.82 (dd,J=8.4, 1.0 Hz, 1H), 7.55-7.50 (m, 1H), 7.35-7.29 (m, 1H), 7.26-7.18 (m,2H), 6.92 (t, J=7.4 Hz, 1H), 6.79 (dd, J=8.7, 0.9 Hz, 2H), 5.57 (s, 2H),5.07 (t, J=5.9 Hz, 2H), 5.00 (s, 2H), 4.47 (t, J=5.9 Hz, 2H), 3.71 (m,2H), 3.55 (m, 2H), 3.31 (s, 3H);

[0934]¹³C NMR (75 MHz, CDCl₃) 158.9, 152.3, 150.3, 146.2, 135.2, 130.3,128.3, 128.2, 127.6, 123.1, 122.2, 120.6, 116.1, 115.1, 72.1, 70.2,66.6, 66.3, 59.3, 45.6;

[0935] MS (CI) m/e 393.1912 (393.1927 calcd for C₂₂H₂₅N₄O₃, M+H);

[0936] Anal calcd for C₂₂H₂₄N₄O₃: C, 67.33; H, 6.16; N, 14.27. Found: C,67.62; H, 6.24; N, 14.37.

Example 137

[0937]2-(Cyclopropylmethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0938] N⁴-(2-phenoxyethyl)quinoline-3,4-diamine (1.7 g, 6.1 mmol) andcyclopropylacetyl chloride (0.86 ml, 7.3 mmol) were combined and treatedaccording to the general procedure described in Example 130.Recrystallization from methanol provided 0.86 g of2-(cyclopropylmethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 191.7-192.6° C.

[0939]¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d, J=7.5 Hz, 1H), 7.63 (dd,J=8.3, 1.1 Hz, 1H), 7.46-7.41 (m, 1H), 7.28-7.19 (m, 3H), 6.89 (t, J=7.3Hz, 1H), 6.79 (d, J=7.8 Hz, 2H), 6.49 (s, 2H), 4.98 (t, J=5.0 Hz, 2H),4.42 (t, J=5.0 Hz, 2H), 2.99 (d, J=6.7 Hz, 2H), 1.40-1.26 (m, 1H), 0.55(m, 2H), 0.32 (m, 2H);

[0940]¹³C NMR(75 MHz, DMSO-d₆) 158.6, 154.1, 152.4, 145.5, 133.1, 130.1,127.0, 126.9, 121.5, 120.8, 115.2, 114.7, 72.1, 66.6, 44.5, 31.1, 9.0,4.6;

[0941] Anal calcd for C₂₂H₂₂N₄O*0.1H₂O: C, 73.35; H, 6.21; N, 15.55.Found: C, 73.23; H, 6.31; N, 15.57.

Example 1382-(2-Cyclopentylethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0942]

[0943] According to the general procedure described in Part C of Example129, 3-cyclopentylpropionyl chloride (1.3 ml, 8.6 mmol) was reacted withN⁴-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol). The productof this reaction was treated according to the general proceduresdescribed in Parts D-F of Example 129. Recrystallization fromacetonitrile provided 0.44 g of the final product,2-(2-cyclopentylethyl)-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine,as a white powder, m.p. 165.0° C.

[0944]¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d, J=8.0 Hz, 1H), 7.64 (dd,J=8.3, 0.80 Hz, 1H), 7.44 (t, J=7.3 Hz, 1H), 7.29-7.20 (m, 3H), 6.90 (t,J=7.3 Hz, 1H), 6.81 (d, J=7.9 Hz, 2H), 6.60 (s, 2H), 4.97 (t, J=4.6 Hz,2H), 4.44 (t, J=4.6 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 1.91-1.77 (m, 5H),1.64-1.48 (m, 4H), 1.20-1.14 (m, 2H);

[0945]¹³C NMR (75 MHz, CDCl₃) 158.2, 155.0, 151.5, 144.7, 133.6, 129.9,127.5, 127.4, 127.0, 122.6, 121.9, 119.5, 115.5, 114.5, 66.0, 45.7,39.8, 33.9, 32.3, 26.4, 24.9;

[0946] MS(CI) m/e 401.2336 (401.2341 calcd for C₂₅H₂₉N₄O, M+H);

[0947] Anal calcd for C₂₅H₂₈N₄O: C, 74.97; H, 7.05; N, 13.99. Found: C,74.67; H, 7.11; N, 13.97.

Example 1391-(2-Phenoxyethyl)-2-tetrahydrofuran-3-yl-1H-imidazo[4,5-c]quinolin-4-amine

[0948]

[0949] N⁴-(2-phenoxyethyl)quinoline-3,4-diamine (1.6 g, 5.7 mmol) andtetrahydrofuran-3-carbonyl chloride (0.98 ml, 7.3 mmol) were combinedand treated according to the general procedure described in Example 130.Recrystallization from acetonitrile provided 0.3 g of1-(2-phenoxyethyl)-2-tetrahydrofuran-3-yl-1H-imidazo[4,5-c]quinolin-4-amineas a tan solid, m.p. 235.9-236.3° C.

[0950]¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=7.8 Hz, 1H), 7.63 (dd,J=8.3, 1.0 Hz, 1H), 7.44 (dd, J=7.6, 1.0 Hz, 1H), 7.29-7.20 (m, 3H),6.90 (t, J=7.3 Hz, 1H), 6.81 (d, J=7.9 Hz, 2H), 6.49 (s, 2H), 5.05 (t,J=4.9 Hz, 2H), 4.42 (t, J=4.9 Hz, 2H), 4.24 (m, 1H), 4.04-3.98 (m, 3H),3.92-3.87 (m, 1H), 2.50-2.30 (m, 2H);

[0951]¹³C NMR(75 MHz, DMSO-d₆) 158.6, 155.2, 152.4, 145.5, 133.2, 130.1,127.0, 126.9, 121.6, 120.3, 115.2, 114.7, 72.1, 68.0, 66.5, 44.4, 36.0,32.4;

[0952] MS(CI) m/e 375.1808 (375.1821 calcd for C₂₂H₂₃N₄O₂, M+H);

[0953] Anal calcd for C₂₂H₂₂N₄O₂*0.25H₂O: C, 69.73; H, 5.98; N, 14.78.Found: C, 69.90; H, 5.91; N, 14.90.

Example 1401-(2-Phenoxyethyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine

[0954]

[0955] According to the general procedure described in Part C of Example129, benzoyl chloride (1.0 ml, 8.5 mmol) was reacted withN⁴-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol). The productof this reaction was treated according to the general proceduresdescribed in Parts D-F of Example 129. Recrystallization from methanolprovided 0.74 g of the final product,1-(2-phenoxyethyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine, as a tansolid, m.p. 182.5-184.6° C.

[0956]¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (d, J=7.9 Hz, 1H), 7.83-7.79 (m,2H), 7.68-7.58 (m, 4H), 7.48 (t, J=7.3 Hz, 1H), 7.29 (t, J=7.3 Hz, 1H),7.16 (m, 2H), 6.85 (t, J=7.3 Hz, 1H), 6.68 (m, 4H), 5.02 (t, J=5.1 Hz,2H), 4.33 (t J=5.1 Hz, 2H);

[0957]¹³C NMR (75 MHz, DMSO-d₆) 158.2, 153.6, 152.9, 146.0, 133.6,131.1, 130.8, 130.3, 130.1, 129.3, 127.9, 127.5, 127.1, 121.9, 121.6,121.2, 115.4, 114.7, 66.1, 45.6;

[0958] MS(CI) m/e 381.1703 (381.1715 calcd for C₂₄H₂₁N₄O, M+H);

[0959] Anal calcd for C₂₄H₂₀N₄O*0.25H₂O: C, 74.88; H, 5.37; N, 14.55.Found: C, 74.42; H, 5.10; N, 14.48.

Example 1414-{[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]methyl}benzonitrile

[0960]

[0961] Part A

[0962] 2-(1H-imidazo[4,5-c]quinolin-1-yl)-1-butanol (3.0 g, 12.4 mmol)was added to a stirring mixture of α-bromo-p-tolunitrile (3.0 g, 15.3mmol), sodium hydroxide (40 ml, 50%), dichloromethane (40 ml), andbenzyltrimethylammonium chloride (0.02 g, 0.11 mmol). The reaction wasmaintained for 72 hours and then diluted with dichloromethane (100 ml)and water (100 ml). The phases were separated and the aqueous phase wasextracted with additional dichloromethane (100 ml). The organicfractions were combined, washed with water, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 9/1 dichloromethane/methanol, R_(f) 0.48) toprovide 2.66 g of4-{[2-(1H-imidazo[4,5-c]quinolin-1-yl)butoxy]methyl}benzonitrile.

[0963] Part B

[0964] 3-Chloroperoxybenzoic acid (2.2 g, 7.5 mmol, 60% by weight) wasslowly added to a solution of4-{[2-(1H-imidazo[4,5-c]quinolin-1-yl)butoxy]methyl}benzonitrile (2.6 g,7.3 mmol) in chloroform (70 ml). The reaction was maintained for 2 hoursand then sequentially washed with saturated sodium bicarbonate (200 ml),water (2×100 ml); dried (MgSO₄); filtered; and concentrated to provide2.7 g of the 5N-oxide product.

[0965] Part C

[0966] p-Toluenesulfonyl chloride (1.43 g, 7.5 mmol) was slowly addedover a 20 minute period to a chilled (0° C.) mixture of the product fromPart B (2.7 g, 7.3 mmol), concentrated ammonium hydroxide (10 ml) anddichloromethane (20 ml). Monitoring by thin layer chromatography (9:1dichloromethane/methanol) indicated that the reaction was completewithin minutes. The reaction was warmed to ambient temperature and thephases were separated. The organic phase was sequentially washed withsodium carbonate (3×), water, and brine; dried (Na₂SO₄); andconcentrated in vacuo. Purification of the resulting brown oil by flashcolumn chromatography (silica gel, 92/8 dichloromethane/methanol)followed by multiple recrystallizations from ethyl acetate/hexaneyielded 0.45 g of4-{[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]methyl}benzonitrileas a tan powder, m.p. 160.0-161.0° C.

[0967]¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.20 (d, J=7.3 Hz, 1H),7.67 (m, 3H), 7.44 (t, J=7.3 Hz, 1H), 7.31-7.21 (m, 3H), 6.72 (s, 2H),5.26 (broad s, 1H), 4.54 (s, 2H), 4.02-3.91 (m, 2H), 2.07 (m, 2H), 0.87(t, J=7.3 Hz, 3H);

[0968]¹³C NMR (125 MHz, DMSO-d₆) 152.2, 145.2, 143.8, 140.1, 132.4,132.0, 127.5, 126.6, 126.4, 121.0, 120.5, 118.7, 115.0, 110.0;

[0969] MS (EI) m/e 371.1754 (371.1746 calcd for C₂₂H₂₁N₅O);

[0970] Anal calcd for C₂₂H₂₁N₅O: C, 71.14; H, 5.70; N, 18.85. Found: C,70.78; H, 5.65; N, 18.51.

Example 1424-({[(2R)-2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]oxy}methyl)benzonitrile

[0971]

[0972] (2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (1.36 g, 5.3mmol) was reacted according to the general procedures described in PartsA and B of Example 141 to provide 1.60 g of the 5N-oxide product.

[0973] Trichloroacetyl isocyanate (0.77 ml, 6.5 mmol) was added dropwiseto a solution of the 5N-oxide (1.60 g) and dichloromethane (25 ml). Thereaction was maintained overnight and then concentrated in vacuo. Theresulting red oil was dissolved in methanol (25 ml) and sodium methoxide(4.0 ml, 21% in methanol) was added dropwise. The reaction wasmaintained for 2.5 days. The solvent was removed in vacuo and the crudeproduct was purified by flash column chromatography (silica gel, 92/8dichloromethane/methanol) followed by recrystallization from methylacetate to yield4-({[(2R)-2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]oxy}methyl)benzonitrileas a white solid. The enantiomeric excess (ee) of the final product wasdetermined to be greater than 99% based on liquid chromatography(column: CHIRALCEL® OD-RH; eluent: 90/10/0.2pentane/methanol/triethylamine; flow rate 2 ml/min, R_(t) 7.8 minutes).

[0974]¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.20 (d, J=7.8 Hz, 1H),7.69 (d, J=8.1 Hz, 2H), 7.63 (dd, J=8.3, 1.1 Hz, 1H), 7.45-7.42 (m, 1H),7.31 (d, J=8.1 Hz, 2H), 7.23 (m, 1H), 6.58 (s, 2H), 5.27 (broad s, 1H),4.57 (s, 2H), 4.03 (dd, J=10.3, 6.8 Hz, 1H), 3.93 (dd, J=10.3, 3.9 Hz,1H), 2.09 (m, 2H), 0.89 (t, J=7.3 Hz, 3H);

[0975] Anal calcd for C₂₂H₂₁N₅O: C, 71.14; H, 5.70; N, 18.85. Found: C,71.00; H, 5.66; N, 18.64.

Example 1434-({[(2S)-2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]oxy}methyl)benzonitrile

[0976]

[0977] (2S)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (1.3 g) wasreacted according to the general procedure described in Example 142.Recrystallization of the final product from ethyl acetate/hexanesprovided 0.2 g of4-({[(2S)-2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]oxy}methyl)benzonitrileas a white solid. The enantiomeric excess (ee) of the final product wasdetermined to be greater than 99% based on liquid chromatography(column: CHIRALCEL® OD-RH; eluent: 90/10/0.2pentane/methanol/triethylamine; flow rate 2 m/min, R_(t) 8.7 minutes).

[0978]¹H NMR (500 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.20 (d, J=8.0 Hz, 1H),7.70 (d, J=8.2 Hz, 2H), 7.63 (dd, J=8.3, 1.1 Hz, 1H), 7.46-7.41 (m, 1H),7.31 (d, J=8.2 Hz, 2H), 7.23 (m, 1H), 6.62 (s, 2H), 5.27 (broad s, 1H),4.57 (s, 2H), 4.04 (dd, J=10.3, 6.7 Hz, 1H), 3.93 (dd, J=10.3, 3.9 Hz,1H), 2.10 (m, 2H), 0.88 (t, J=7.3 Hz, 3H);

[0979] Anal calcd for C₂₂H₂₁N₅O: C, 71.14; H, 5.70; N, 18.85. Found: C,71.10; H, 5.98; N, 18.96.

Example 1442-(2-Methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0980]

[0981] Part A

[0982] Propargyl bromide (10.0 ml, 89.8 mmol, 80% in toluene) andbenzyltrimethylammonium chloride (0.60 g, 3.2 mmol) were dissolved indichloromethane (130 ml). The solution was treated with sodium hydroxide(130 ml, 50% w/w in water).2-[2-(2-Methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (20.0 g,73.7 mmol) was added and the mixture was vigorously stirred for 18hours. Thin layer chromatography (9/1 chloroform/methanol) indicatedcomplete conversion. The mixture was diluted with water (200 ml) and thephases were separated. The aqueous fraction was extracted withadditional dichloromethane (3×150 ml). The combined organic fractionswere washed with brine (100 ml), dried (Na₂SO₄), filtered andconcentrated to yield 22.7 g of2-(2-methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinolineas an orange solid.

[0983]¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.40 (m, 1H), 8.15 (m,1H), 7.73-7.64 (m, 2H), 4.89 (t, J=5.3 Hz, 2H), 4.10 (d, J=2.4 Hz, 2H),3.95 (t, J=5.1 Hz, 2H), 3.89 (t, J=6.9 Hz, 2H), 3.36 (t, J=2.4 Hz, 1H),3.32 (s, 3H), 3.27 (t, J=6.9 Hz, 2H).

[0984] Part B

[0985]2-(2-Methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline(22.7 g, 73.4 mmol) was dissolved in chloroform (300 ml) and chilled inan ice water bath. 3-Chloroperoxybenzoic acid (17.0 g, 127.9 mmol, 77%max) was added in small portions over 30 minutes. Analysis by thin layerchromatography (9/1 chloroform/methanol) at 30 minutes indicated thatthere was still starting material present. Additional3-chloroperoxybenzoic acid (7.00 g, 52.7 mmol, 77% max) was added. After2 hours, the reaction was warmed to ambient temperature and quenched bythe addition of saturated sodium bicarbonate (100 ml). The aqueous andorganic fractions were separated and the aqueous fraction was extractedwith additional chloroform (2×50 ml). The combined organic fractionswere washed with water (100 ml), brine (100 ml); dried (Na₂SO₄);filtered; and concentrated in vacuo to provide a dark orange solid. ¹HNMR indicated less than 5% 3-chlorobenzoic acid in the crude product.The material was used without further purification.

[0986]¹H NMR (300 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.33 (d, J=7.7 Hz, 1H),7.99 (d, J=7.3 Hz, 1H), 7.38-7.30 (m, 2H), 4.40 (t, J=4.8 Hz, 2H), 3.63(d, J=2.1 Hz, 2H), 3.47 (t, J=4.9 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 2.88(t, J=2.0 Hz, 1H), 2.84 (s, 3H), 2.78 (t, J=6.3 Hz, 2H).

[0987] Part C

[0988] Under an atmosphere of nitrogen,2-(2-methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(1.57 g, 4.83 mmol) was dissolved in dichloromethane (25 ml).Trichloroacetyl isocyanate (0.80 ml, 6.71 mmol) was added dropwise viasyringe. The reaction was stirred for 1 hour and then the volatiles wereremoved in vacuo. The resulting residue was treated with methanol (15ml) forming an orange suspension. A solution of sodium methoxide (25% inmethanol) was added slowly via syringe. The reaction became a darkorange solution. After 1.5 hours the reaction was quenched by the slowaddition of saturated ammonium chloride solution (10 ml). The methanolwas removed in vacuo. The aqueous residue was extracted withdichloromethane (3×10 ml) and the organic fractions were combined andwashed with water (10 ml) and brine (10 ml). The solution was dried(Na₂SO₄), filtered and concentrated in vacuo to yield the crude productas an orange solid. Recrystallization from propyl acetate provided 0.78g of2-(2-methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amineas off-white crystals.

[0989]¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, J=7.3 Hz, 1H), 7.61 (d, J=7.2Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.23 (t, J=7.3 Hz, 1H), 6.44 (bs, 2H),4.78 (t, J=5.2 Hz, 2H), 4.11 (d, J=2.5 Hz, 2H), 3.91 (t, J=5.5 Hz, 2H),3.83 (t, J=6.7 Hz, 2H), 3.37 (t, J=2.6 Hz, 1H), 3.30 (s, 3H), 3.20 (t,J=6.8 Hz, 2H);

[0990] MS (CI) m/e 325 (M+H);

[0991] Anal calcd for C₁₈H₂₀N₄O₂: C, 66.65; H, 6.21; N, 17.27. Found: C,66.34; H, 6.05; N, 16.96.

Example 145 2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0992]

[0993] Part A

[0994] Using the general method of Example 1 Part B,2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (12.0 g, 44.56mmol) was oxidized to provide 8.7 g of2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate as abrown solid. Material was used without further purification.

[0995] Part B

[0996] A dried round bottom flask was charged with a stir bar,2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (8.7 g,30.49 mmol), anhydrous dimethylformamide (80 mL), and anhydrous toluene(100 mL) under nitrogen. To this brown mixture was added phosphorusoxychloride (3.1 mL) by syringe at ambient temperature. The reactionsolution cleared in a couple of minutes and a slight exotherm wasobserved. The reaction was judged to be complete after 30 minutes. Thevolatiles were removed under reduced pressure. The resulting brown solidwas partitioned between dichloromethane and 4% aqueous sodiumbicarbonate to a pH of 8. The aqueous layer was extracted withdichloromethane (5×). The organic fractions were combined, dried withanhydrous sodium sulfate, concentrated under reduced pressure and driedovernight at ambient temperature under reduced pressure to provide 9.2 gof 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate asa brown oil.

[0997] MS(CI) for C₁₅H₁₄ClN₃O₂ m/z 304 (MH⁺), 262, 218

[0998] Part C

[0999] A round bottom flask was charge with a stir bar,2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (9.2g, 30.5 mmol), methanol (200 mL) and potassium carbonate (0.4 g, 3.0mmol). The reaction was judged complete after stirring for 5 hours at26° C. The solution was partitioned between chloroform and brine. Theorganic layer was removed and the aqueous fraction extracted withchloroform (6×). The organic fractions were combined, dried withanhydrous sodium sulfate and concentrated under reduced pressure toapproximately 200 mL when crystallization was observed. The solution wasstoppered and maintained at ambient temperature for 24 hours. Theresulting fine white crystals were collected by filtration to provide4.49 g of 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol.

[1000] MS(CI) for C₁₃H₁₂ClN₃O m/z 262 (MH⁺), 218

[1001] Part D

[1002] A round bottom flask was charge with a stir bar,2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (3.9 g, 14.9mmol), dichloromethane (125 mL), aqueous sodium hydroxide (50%, 125 mL),benzyltrimethylammonium chloride (0.55 g, 0.003 mmol) and stirredvigorously at ambient temperature. To this mixture was added cinnamylbromide (8.8 g, 44.71 mmol) as a solid. After 45 minutes the solutionwas clear and the reaction was judged complete. The solution was pouredinto ice water (200 mL), the organic layer separated and was drawn off.The aqueous solution was extracted with dichloromethane (4×). Theorganic layers were combined, washed with brine, dried with anhydroussodium sulfate, and concentrated under reduced pressure. The resultingorange oil was purified by chromatography over silica gel(dichloromethane, followed by 98/2 dichloromethane/methanol). Theresulting oil was triturated with ethyl ether and the resulting solidwas collected by filtration and dried to provide 4.22 g of4-chloro-2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline as a white solid.

[1003] MS(CI) for C₂₂H₂₀ClN₃O m/z 378 (MH⁺), 262, 228

[1004] Part E

[1005]4-Chloro-2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline(2.12 g, 5.61 mmol), was combined with an ammonia/methanol solution (7%,70 mL) in a bomb and heated to 150° C. for 16.5 hours and cooled toambient temperature. Analysis indicated that the reaction wasincomplete. The solution was concentrated under reduced pressure to ˜10mL, diluted with ammonia/methanol (7%, 50 mL) and reacted in a bomb at150° C. for 8.5 hours to complete the reaction. The solution waspartitioned between dichloromethane and saturated aqueous sodiumbicarbonate and the organic layer removed. The aqueous layer wassaturated with sodium chloride and extracted with dichloromethane (3×).The organic fractions were combined, dried with anhydrous sodium sulfateand concentrated under reduced pressure. The resulting brown solid wasrecrystalized from methanol to provide 0.963 g of2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 111.8-112.5° C.

[1006] Analysis. Calculated for C₂₂H₂₂N₄O: % C, 73.72; % H, 6.19; % N,15.63. Found: % C, 73.48; % H, 6.25; % N, 15.57

[1007]¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, J=7.5 Hz, 1H), 7.61 (d, J=8.1Hz, 1H), 7.40 (t, J=5.6 Hz, 1H), 7.18-7.30 (m, 6H), 6.51 (s, 2H), 6.31(d, J=16.2 Hz, 1H), 6.17 (dt, J=15.6, 5.3 Hz, 1H), 4.76 (t, J=5.0 Hz,2H), 4.05 (d, J=3.9 Hz, 2H), 3.91 (t, J=5.6, 2H), 2.64 (s, 3H)

[1008] MS(CI) for C₂₂H₂₂N₄O m/z 259 (MH⁺), 243, 199

Example 1462-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine

[1009]

[1010] Part A

[1011] Using the general method of Example 115 Part C, the 4-amino groupwas introduced to2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (8.47g, 29.71 mmol). The resulting brown oil was purified by trituration withacetonitrile and dried to yield 3.583 g of2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate as atan solid.

[1012] MS(CI) for C₁₅H₁₆ClN₄O₂ m/z 285 (MH⁺), 270, 199

[1013] Part B

[1014] A Parr flask was charged with2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (3.61g, 12.64 mmol), trifluoroacetic acid (50 mL) and purged with nitrogen.To this solution was added platinum(IV) oxide (0.5 g). The reaction wasjudged to be complete after 13 days of hydrogenation at ambienttemperature. The solution was filtered and the volatiles removed underreduced pressure. The resulting brown oil was partitioned betweendichloromethane and saturated aqueous sodium bicarbonate to a pH of ˜8.The layers were separated. The aqueous layer was extracted withdichloromethane (4×). The organic fractions were combined, dried withanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting white solid was purified by recrystallization from ethylacetate/methanol (9/1) and dried to provide 0.98 g of2-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)ethanolas a white solid.

[1015] MS (CI) for C₁₃H₁₈N₄O m/z 247 (MH⁺), 203

[1016] Part C

[1017] Using the general method of Example 1 Part A,2-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)ethanol(0.763 g, 3.098 mmol) was reacted with propargyl bromide (80% intoluene, 1.1 mL, 9.29 mmol) to provide 0.42 g of2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas a brown oil.

[1018] MS (CI) for C₁₆H₂₀N₄O m/z 285 (MH⁺), 247, 183

[1019] Part D

[1020] Using the general method of Example 12 Part A,2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(0.396 g, 1.392 mmol) was reacted with iodobenzene (0.17 mL, 1.532 mmol)at ambient temperature. After 18 hours the reaction was incomplete. Thesolution was heated to 50° C. for 3 hours to complete the reaction. Thevolatiles were removed under reduced pressure. The resulting oil waspartitioned between dichloromethane and 4% aqueous sodium carbonate andthe organic layer removed. The aqueous layer was extracted withdichloromethane (3×). The organic fractions were combined, dried withanhydrous sodium sulfate and the volatiles were removed under reducedpressure. The resulting oil was purified by chromatography over silicagel (95/5 dichloromethane/methanol). The resulting white solid wasdissolved in dichloromethane (2 mL) and reacted with 1M HCl in ether (2mL). The volatiles were removed under reduced pressure and the resultingsolids recrystallized from methanol to provide 0.1089 g of2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(hydrochloride)_(1.9)as a tan solid.

[1021] Analysis. Calculated for C₂₂H₂₄N₄O(HCl)_(1.9) (H₂O)_(0.7): % C,59.74; % H, 6.22; % N, 12.67; % Cl, 15.23. Found: % C, 59.72; % H, 6.04;% N, 12.65; % Cl, 14.99

[1022]¹H NMR (300 MHz, DMSO-d₆) δ 7.93 (s, 2H), 7.36-7.40 (m, 3H),7.28-7.30 (m, 2H), 4.56 (t, J=5.0 Hz, 2H), 4.35 (s, 2H), 3.88 (t, J=5.3Hz, 2H), 2.92 (s, 2H), 2.69 (s, 2H), 2.60 (s, 3H), 1.73 (s, 4H)

[1023] MS(CI) for C₂₂H₂₄N₄O m/z 361 (MH⁺), 247, 199

Example 1472-Methyl-1-{3-[(3-phenylprop-2-ynyl)oxy]propyl}-H-imidazo[4,5-c]quinolin-4-amine

[1024]

[1025] Part A

3-(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl(Prop-2-ynyl) Ether

[1026] To 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-propanol (12.2g, 50.56 mmol) dissolved in dichloromethane (180 mL) was added sodiumhydroxide (180 mL of 50%) with mechanical stirring.Benzyltrimethylammonium chloride (1.88 g, 10.11 mmol) was added to theresulting suspension, and after stirring for 5 minutes, propargylbromide (17 mL of 80% in toluene, 141.8 mmol) was added. The resultingreaction mixture was allowed to stir at ambient temperature. After 2hours, TLC monitoring indicated 50% completion, and after 4.5 hours HPLCmonitoring indicated 20% starting material remaining. More propargylbromide (5 mL of 80% in toluene, 40.51 mmol) was added, and theresulting reaction mixture was allowed to stir at ambient temperaturefor 64.5 hours. The layers were separated, and the organic layer waswashed with water (3×) and brine, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The resulting dark oil wasdissolved in dichloromethane and again extracted with water, dried oversodium sulfate, and concentrated under reduced pressure. The resultingdark oil was purified by silica gel column chromatography using 98/2dichloromethane/methanol as the eluant. After removing the solvent fromthe collected fractions, 5.880 g of pure (by HNMR analysis) product wasobtained. This material was recrystallized from ethyl acetate/hexane toprovide 4.658 g of brown crystals.

[1027] Part B

[1028]3-(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl(3-Phenylprop-2-ynyl)Ether

[1029] Under a nitrogen atmosphere, a mixture of3-(2-methyl-1H-Imidazo[4,5-c]quinolin-1-yl)propyl(prop-2-ynyl) ether(4.6585 g, 16.68 mmol) from Part A, anhydrous acetonitrile (60 mL),anhydrous triethylamine (6 mL, 43.37 mmol), and iodobenzene (2.1 mL,18.34 mmol) was heated to 80° C. with stirring.Dichlorobis(triphenylphosphine)palladium(II) (0.23 g, 0.334 mmol), andcopper(I) iodide (0.13 g, 0.667 mmol) were added and the mixture wasallowed to stir for 0.5 hour. Analysis by HPLC indicated that thereaction was complete. The reaction mixture was concentrated underreduced pressure, and the concentrate was purified by columnchromatography over silica gel, employing dichloromethane (1 L) and 98/2dichloromethane/methanol as the eluants. The resulting green oil (5.1 g)was triturated with ether, but no solids formed. The oil was placedunder high vacuum (4 torr) at room temperature. ¹HNMR analysis of theresulting oil showed the presence of ether. The oil was further driedunder high vacuum to provide 4.7 g of dark oil.

[1030] Part C

[1031]2-Methyl-1-[3-(3-phenylprop-2-ynyloxy)propyl-1H-imidazo[4,5-c]quinoline-5N-oxide

[1032]3-(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl(3-phenylprop-2-ynyl)ether (4.7 g, 13.22 mmol) and dichloromethane were combined, and3-chloroperoxybenzoic acid (4.87 g of dry material) was added in asingle portion. After the mixture was stirred for 40 minutes, TLCanalysis using 9/1 dichloromethane/methanol indicated that the reactionwas complete. This was confirmed by HPLC and HNMR analyses. The product,2-methyl-1-[3-(3-phenylprop-2-ynyloxy)propyl]-1H-imidazo[4,5-c]quinoline-5N-oxide,was confirmed by HPLC and LC-MS. The resulting solution was used as isin the next step.

[1033] Part D

[1034]2-Methyl-1-{3-[(3-phenylprop-2-ynyl)oxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine

[1035] To the solution from Part C was added ammonium hydroxide (50 mL)with vigorous stirring. p-Toluenesulfonyl chloride (2.77 g, 14.54 mmol)was added as a dry solid to the resulting solution over a 2 minuteperiod to prevent excessive foaming. After 40 minutes, the reaction wasjudged to be complete by TLC analysis using 9/1dichloromethane/methanol. The resulting reaction mixture was dilutedwith water and extracted with dichloromethane. The combined organiclayers were washed with brine, dried over sodium sulfate, and filtered.The resulting filtrate was concentrated under reduced pressure toprovide 4.9 g of brown solid, which was purified by columnchromatography over silica gel using dichloromethane (1 L) and 95/5dichloromethane/methanol as the eluants. A brown oil (3.8 g) wasisolated and triturated with acetonitrile, causing a solid to form after30 minutes. The solid was collected by filtration, and washed withether. HNMR analysis of the resulting solid was consistent with thedesired product that contained residual acetonitrile and ether. Thesolid was dried to provide 2.308 g of2-methyl-1-{3-[(3-phenylprop-2-ynyl)oxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine,m.p. 160.0-161.6° C.

[1036] Analysis: Calculated for C₂₃H₂₂N₄O: % C, 74.57; % H, 5.99; % N,15.12. Found: % C, 74.27; % H, 5.94; % N, 15.10

[1037]¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.5Hz, 1H), 7.38-7.47 (m, 6H), 7.24 (t, J=6.9 Hz, 1H), 6.53 (s, 2H), 4.60(t, J=7.2 Hz, 2H), 4.45 (s, 2H), 3.60 (t, J=5.6 Hz, 2H), 2.63 (s, 3H),2.14 (p, J=6.5 Hz, 2H).

Example 1482-Methyl-1-[3-(3-phenylpropoxy)propyl]-1H-imidazo[4,5-c]quinolin-4-amine

[1038]

[1039]2-Methyl-1-{3-[(3-phenylprop-2-ynyl)oxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine(1.4 g, 3.779 mmol) was combined with toluene (15 mL) in a Parr flaskand heated to reflux. The resulting solution was cooled to roomtemperature and purged with nitrogen. Palladium (0.6 g 10% palladium oncarbon) was added to the solution under nitrogen, and the flask waspressurized with hydrogen at 310 kPa for 2.75 hours. Monitoring by HNMRindicated incomplete reaction. More 10% palladium on carbon (0.16 g) wasadded, and after an additional 2.5 hours at 310 kPA of hydrogen, thereaction was determined to be complete. The catalyst was filtered off,and the volatiles were removed under reduced pressure. The resultingwhite solid was recrystallized from acetonitrile and dried for 5 days toprovide 1.0723 g of2-methyl-1-[3-(3-phenylpropoxy)propyl]-1H-imidazo[4,5-c]quinolin-4-amine,m.p. 145.0-146.1° C.

[1040] Analysis: Calculated for C₂₃H₂₆N₄O: % C, 73.77; % H, 7.00; % N,14.96. Found: % C, 73.50; % H, 6.92; % N, 14.86

[1041]¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=8.1 Hz, 1H), 7.60 (d,J=10.0 Hz, 1H), 7.40 (t, J=7.4 Hz, 1H), 7.15-7.31 (m, 6H), 6.49 (s, 2H),4.58 (t, J=7.5 Hz, 2H), 3.39-3.47 (m, 4H), 2.67 (t, J=7.8 Hz, 2H), 2.60(s, 3H), 2.08 (p, J=6.2 Hz, 2H), 1.86 (p, J=7.0 Hz, 2H).

Example 1492-Methyl-1-{4-[(3-phenylprop-2-ynyl)oxy]butyl}-1H-imidazo[4,5-c]quinolin-4-amine

[1042]

[1043] Part A

[1044] 4-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl(Prop-2-ynyl)Ether

[1045] To 4-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-butanol (1 g,3.917 mmol), dichloromethane (14 mL), sodium hydroxide (14 mL of 50%),and benzyltrimethylammonium chloride (0.15 g, 0.783 mmol) were combinedwith stirring. Propargyl bromide (1.3 mL of 80% in toluene, 11.75 mmol)was added to the resulting mixture at ambient temperature. After theresulting reaction mixture was allowed to stir at ambient temperaturefor 1 hour, TLC analysis using 9/1 dichloromethane/methanol indicatedincomplete reaction. After 18 hours HPLC monitoring indicated completereaction. The two reaction layers were separated. The organic layer waswashed with water (3×100 mL). All aqueous layers were combined andextracted with dichloromethane (3×100 mL). All organic layers werecombined and washed with brine (3×100 mL). The brine layers werecombined and extracted with dichloromethane (3×100 mL). All resultingorganic layers were combined, dried with sodium sulfate, filtered, andconcentrated under reduced pressure. HNMR analysis of the resulting darkoil was consistent with the desired product and some residual solvent.HPLC and LC/MS were consistent with the desired product (1.1 g) that wasof sufficient purity for use in the next step.

[1046] Part B

[1047]4-(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl(3-Phenylprop-2-ynyl)Ether

[1048] 4-(2-Methyl-1H-Imidazo[4,5-c]quinolin-1-yl)butyl(prop-2-ynyl)ether (1.1 g, 3.75 mmol) from Part A, anhydrous acetonitrile (10 mL),anhydrous triethylamine (1.4 mL, 9.75 mmol), and iodobenzene (0.5 mL,4.12 mmol) were combined and heated to 80° C.Dichlorobis(triphenylphosphine)palladium(II) (0.05 g, 0.07 mmol), andcopper(I) iodide (0.03 g, 0.15 mmol) were added to the resultingsolution, and the mixture was allowed to stir for 0.5 hour. Analysis byHPLC indicated that the reaction was complete. The resulting reactionmixture was allowed to cool to ambient temperature, and filtered. Thefiltrate, which still contained a fine precipitate, was plug filteredthrough a silica gel column using dichloromethane and 98/2dichloromethane/methanol as the eluants. Two fractions were collectedand, after removing the volatiles under reduced pressure, an oil wasisolated from each. The oils were dried separately under high vacuum toprovide 0.4525 g of a first oil and 0.2506 g of a second oil. HNMRanalysis of the first oil indicated residual methanol and of the secondoil showed residual iodobenzene and ethyl acetate. The two oils werecarried on separately to the next step.

[1049] Part C

[1050]2-Methyl-1-[4-(3-phenylprop-2-ynyloxy)butyl]-1H-imidazo[4,5-c]quinoline-5N-oxide

[1051] The first oil from Part B,4-(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl(3-phenylprop-2-ynyl)ether (0.4525 g, 1.225 mmol) and dichloromethane (5 mL) were combined,and then 3-chloroperoxybenzoic acid (0.45 g of 75%, 1.959 mmol) wasadded. After the resulting mixture was stirred for 1 hour, HNMR analysisindicated that the reaction was complete. The reaction mixture wasextracted with saturated aqueous potassium carbonate. The resultingaqueous layer was extracted with dichloromethane. All organic layerswere combined, washed with brine, dried over sodium sulfate, filtered,and concentrated under reduced pressure to provide 0.6068 g of undriedproduct,2-methyl-1-[4-(3-phenylprop-2-ynyloxy)butyl]-1H-imidazo[4,5-c]quinoline-5N-oxide.This was confirmed by HNMR. The resulting solution was used in the nextstep without further purification.

[1052] The above procedure was repeated using the second oil (0.2506 g)from Part B, and 0.25 g of the 3-chloroperoxybenzoic acid to provide0.3749 g of undried product.

[1053] Part D

[1054]2-Methyl-1-{4-[(3-phenylprop-2-ynyl)oxy]butyl}-1H-Imidazo[4,5-c]quinolin-4-amine

[1055] To2-methyl-1-[4-(3-phenylprop-2-ynyloxy)butyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(9.2 g, 23.87 mmol) dissolved in dichloromethane (50 mL) was addedammonium hydroxide (25 mL of 27%) with vigorous stirring in a 1 L flask(for sufficient head room for foaming). p-Toluenesulfonyl chloride (5.00g, 26.25 mmol) was added in a single portion to the resulting solution,and foaming occured. After stirring at ambient temperature for 20minutes, the reaction was judged to be complete by TLC, HPLC, and LC/MS.The resulting reaction mixture was mixed with 1N potassium hydroxide.Brine was added to the resulting emulsion, and the organic layerseparated from the aqueous layer. The aqueous layer was washed withdichloromethane (5×). All organic layers were combined, washed withbrine, dried with sodium sulfate, filtered, and concentrated underreduced pressure. The resulting dark brown residue was triturated withdichloromethane/ether, and the resulting tan solid was collected byvacuum filtration and dried in a vacuum desicator for 2 days. HNMRanalysis of the resulting tan solid (5.1733 g) was consistent with thedesired product. A portion of this tan solid (2 g) was used in Example150 and the remainder was recrystallized from toluene. Therecrystallized material was dissolved in dichloromethane, and theresulting solution was washed with 0.1 N potassium hydroxide, water, andbrine, dried with sodium sulfate, and concentrated under reducedpressure to dryness. The resulting solid was recrystallized from tolueneand dried at 60° C. for 4 days under high vacuum to provide 2.0028 g of2-methyl-1-{4-[(3-phenylprop-2-ynyl)oxy]butyl}-1H-imidazo[4,5-c]quinolin-4-amine,m.p. 109.2-110.0° C.

[1056] Analysis: Calculated for C₂₄H₂₄N₄O: % C, 74.97; % H, 6.29; % N,14.57. Found: % C, 74.75; % H, 6.28; % N, 14.49

[1057]¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.1Hz, 1H), 7.34-7.43 (m, 6H), 7.26 (t, J=7.8 Hz, 1H), 6.49 (s, 2H), 4.54(t, J=7.5 Hz, 2H), 4.39 (s, 2H), 3.59 (t, J=6.2 Hz, 2H), 2.6 (s, 3H),1.91 (p, J=7.5 Hz, 2H), 1.72 (p, J=6.7 Hz, 2H).

Example 150 2-Methyl-1[4-(3-phenylpropoxy)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[1058]

[1059]2-Methyl-1-{4-[(3-phenylprop-2-ynyl)oxy]butyl}-1H-imidazo[4,5-c]quinolin-4-amine(2.00 g, 5.202 mmol) from Example 149 was combined with toluene (15 mL)in a Parr flask and heated to reflux. The resulting solution was purgedwith nitrogen. Palladium (1 g 10% palladium on carbon) was added to thesolution under nitrogen, and the flask was pressurized with hydrogen at310 kPa for 3 hours. Monitoring by HNMR indicated complete reaction. Thecatalyst was filtered off, and the filtrate was concentrated underreduced pressure. The concentrate was dissolved in dichloromethane andbasified with 1 N potassium hydroxide to a pH of about 14. The layerswere separated and the aqueous layer was extracted with dichloromethane(3×). The organic layers were combined, washed with 0.5 N potassiumhydroxide (2×), water (3×), and brine (3×), dried with sodium sulfate,filtered, and concentrated under reduced pressure. The resulting solidwas recrystallized from acetonitrile, and the resulting shinny tancrystals were dried for 2 days, triturated with ether, collected byvacuum filtration, and dried to provide 0.5744 g of 2-methyl-1[4-(3-phenylpropoxy)butyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p.105.1-106.0° C.

[1060] Analysis: Calculated for C₂₄H₂₈N₄O: % C, 74.20; % H, 7.26; % N,14.42. Found: % C, 73.88; % H, 7.33; % N, 14.06

[1061]¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, J=8.1 Hz, 1H), 7.60 (d, J=6.9Hz, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.12-7.26 (m, 6H), 6.50 (s, 2H), 4.52(t, J=7.5 Hz, 2H), 3.41 (t, J=5.9 Hz, 2H), 3.35 (t, J=6.2 Hz, 2H),2.54-2.60 (m, 5H), 1.89 (p, J=7.4 Hz, 2H), 1.76 (p, J=7.0 Hz, 2H), 1.65(p, J=6.6 Hz, 2H).

Cytokine Induction in Human Cells

[1062] An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon and tumornecrosis factor (α) (IFN and TNF, respectively) secreted into culturemedia as described by Testerman et. al. In “Cytokine Induction by theImmunomodulators Imiquimod and S-27609”, Journal of Leukocyte Biology,58, 365-372 (September, 1995).

[1063] Blood Cell Preparation for Culture

[1064] Whole blood from healthy human donors is collected byvenipuncture into EDTA vacutainer tubes. Peripheral blood mononuclearcells (PBMC) are separated from whole blood by density gradientcentrifugation using Histopaque®-1077. Blood is diluted 1:1 withDulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced SaltsSolution (HBSS). The PBMC layer is collected and washed twice with DPBSor HBSS and resuspended at 4×10⁶ cells/mL in RPMI complete. The PBMCsuspension is added to 48 well flat bottom sterile tissue culture plates(Costar, Cambridge, Mass. or Becton Dickinson Labware, Lincoln Park,N.J.) containing an equal volume of RPMI complete media containing testcompound.

[1065] Compound Preparation

[1066] The compounds are solubilized in dimethyl sulfoxide (DMSO). TheDMSO concentration should not exceed a final concentration of 1% foraddition to the culture wells. The compounds are generally tested atconcentrations ranging from 30-0.014 μM.

[1067] Incubation

[1068] The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial 3 fold dilutions are made in thewells. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range(30-0.014 μM). The final concentration of PBMC suspension is 2×10⁶cells/mL. The plates are covered with sterile plastic lids, mixed gentlyand then incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxideatmosphere.

[1069] Separation

[1070] Following incubation the plates are centrifuged for 10 minutes at1000 rpm (˜200×g) at 4° C. The cell-free culture supernatant is removedwith a sterile polypropylene pipet and transferred to sterilepolypropylene tubes. Samples are maintained at −30 to −70° C. untilanalysis. The samples are analyzed for interferon (α) by ELISA and fortumor necrosis factor (α) by ELISA or IGEN Assay.

[1071] Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA

[1072] Interferon (α) concentration is determined by ELISA using a HumanMulti-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J.Results are expressed in pg/mL.

[1073] Tumor necrosis factor (α) (TNF) concentration is determined usingELISA kits available from Biosource International, Camarillo, Calif.Alternately, the TNF concentration can be determined by Origen® M-SeriesImmunoassay and read on an IGEN M-8 analyzer from IGEN International,Gaithersburg, Md. The immunoassay uses a human TNF capture and detectionantibody pair from Biosource International, Camarillo, Calif. Resultsare expressed in pg/mL.

[1074] The table below lists the lowest concentration found to induceinterferon and the lowest concentration found to induce tumor necrosisfactor for each compound. A “*” indicates that no induction was seen atany of the tested concentrations; generally the highest concentrationtested was 10 or 30 μM. Cytokine Induction in Human Cells Example LowestEffective Concentration (μM) Number Interferon Tumor Necrosis Factor 10.12 1.11 2 1.11 * 3 0.12 3.33 4 0.12 * 5 0.12 1.11 6 0.12 * 7 1.11 0.378 1.11 10 9 * * 10 1.11 10 11 1.11 * 12 10 * 13 10 10 14 10 10 15 0.12 *16 0.01 0.37 17 0.12 0.37 18 0.12 1.11 19 0.37 * 20 * * 21 0.12 * 220.12 0.37 23 1.11 * 24 0.12 * 25 0.12 * 26 0.12 * 27 0.12 * 28 10 *29 * * 30 3.33 * 31 * * 32 10 * 33 * * 34 * * 35 * * 36 * * 37 * * 3810 * 39 1.11 * 40 0.12 * 41 1.11 3.33 42 0.37 * 43 0.37 * 45 0.37 * 460.01 3.33 47 0.12 * 48 0.12 * 49 0.04 * 50 3.33 * 51 0.37 * 52 1.11 * 531.11 * 54 0.12 * 55 * * 56 1.11 10 57 * 30 58 3.33 * 59 1.11 * 60 1.11 *61 3.33 * 62 * 3.33 63 * * 64 3.33 * 65 1.11 * 66 * * 67 * 30 68 3.33 *69 1.11 * 70 0.37 * 71 3.33 * 72 1.11 * 73 1.11 * 74 0.37 * 75 * * 761.11 * 77 0.12 * 78 * * 79 * * 80 * * 81 1.11 * 82 * * 83 0.37 * 840.37 * 85 0.37 * 86 0.37 * 87 1.11 * 88 0.37 30 89 0.37 10 90 0.12 10 910.37 10 92 3.33 3.33 93 0.12 10 94 0.01 3.33 95 1.11 * 96 0.12 10 971.11 * 98 0.37 * 99 0.37 * 100 * * 101 0.04 10 102 0.37 * 103 * 10 1040.12 10 105 0.37 1.11 106 0.37 * 108 0.00017 0.04 109 0.01 0.37 1103.33 * 111 3.33 * 112 * * 113 1.11 * 114 0.12 0.37 115 0.12 1.11 116 * *117 * * 118 0.01 0.04 119 0.01 0.12 120 0.01 0.01 121 0.01 0.04 122 0.010.12 123 0.12 10 124 1.11 10 125 0.01 0.37 126 0.04 0.04 127 0.01 0.12128 * * 129 0.01 0.04 130 3.33 3.33 131 * 10 132 0.01 3.33 133 3.33 *134 * * 135 * * 138 1.11 * 139 * * 140 * * 141 0.12 0.12 142 0.04 0.04143 1.11 3.33 144 0.01 0.04 147 0.37 0.37 148 1.11 1.11 149 0.041 0.37150 0.37 1.11

What is claimed is:
 1. A compound of the Formula (I):

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; R₁ is selectedfrom the group consisting of: -alkenyl; -aryl; and —R₄-aryl; R₂ isselected from the group consisting of: -hydrogen; -alkyl; -alkenyl;-aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y-alkenyl;-alkyl-Y-aryl; and alkyl or alkenyl substituted by one or moresubstituents selected from the group consisting of: —OH; -halogen;—N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃; -aryl;-heteroaryl; -heterocyclyl; —CO-aryl; and —CO-heteroaryl; R₄ is alkyl oralkenyl, which may be interrupted by one or more —O— groups; each R₃ isindependently H or C₁₋₁₀ alkyl; each Y is independently —O— or—S(O)₀₋₂—; n is 0 to 4; and each R present is independently selectedfrom the group consisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogenand trifluoromethyl; or a pharmaceutically acceptable salt thereof.
 2. Acompound or salt of claim 1 wherein R₁ is -alkyl-aryl.
 3. A compound orsalt of claim 1 wherein R₁ is —(CH₂)₀₋₃-phenyl.
 4. A compound or salt ofclaim 1 wherein R₁ is —(CH₂)₀₋₃-substituted phenyl.
 5. A compound orsalt of claim 1 wherein X is —CH(alkyl)-alkyl- wherein the alkyl groupscan be the same or different.
 6. A compound or salt of claim 1 wherein Xis —CH₂—CH₂—, —CH₂—CH₂—CH₂—, or —CH₂—CH₂—CH₂—CH₂—.
 7. A compound or saltof claim 1 wherein X is —CH(C₂H₅)—CH₂—.
 8. A compound or salt of claim 1wherein R₂ is H.
 9. A compound or salt of claim 1 wherein R₂ is alkyl.10. A compound or salt of claim 1 wherein R₂ is -alkyl-O-alkyl.
 11. Acompound of the Formula (II)

wherein X is CHR₃—, —CHR₃-alkyl-, or CHR₃-alkenyl-; R₁₀ is selected fromthe group consisting of: —H; -alkyl; -alkylaryl; -alkenyl; and -aryl; R₂is selected from the group consisting of: -hydrogen; -alkyl; -alkenyl;-aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y— alkenyl;-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or moresubstituents selected from the group consisting of: —OH; -halogen;—N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃; -aryl;-heteroaryl; -heterocyclyl; —CO-aryl; and —CO-heteroaryl; n is 0 to 4;each Y is independently —O— or —S(O)₀₋₂—; each R₃ is independently H orC₁₋₁₀ alkyl; and each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen andtrifluoromethyl; or a pharmaceutically acceptable salt thereof.
 12. Acompound of claim 11 wherein R₁₀ is aryl.
 13. A compound or salt ofclaim 11 wherein R₁₀ is —(CH₂)₀₋₃-phenyl.
 14. A compound or salt ofclaim 11 wherein R₁₀ is —(CH₂)₀₋₃-substituted phenyl.
 15. A compound orsalt of claim 11 wherein X is —CH(alkyl)-alkyl-, wherein the alkylgroups can be the same or different.
 16. A compound or salt of claim 11wherein X is —CH₂—CH₂—, —CH₂—CH₂—CH₂—, or —CH₂—CH₂—CH₂—CH₂—.
 17. Acompound or salt of claim 11 wherein X is —CH(C₂H₅)—CH₂—.
 18. A compoundor salt of claim 11 wherein R₂ is H.
 19. A compound or salt of claim 11wherein R₂ is alkyl.
 20. A compound or salt of claim 11 wherein R₂ isalkyl-O-alkyl.
 21. A compound of the Formula (III)

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; R₁ is selectedfrom the group consisting of: -aryl; -alkenyl; and —R₄-aryl; R₂ isselected from the group consisting of: -hydrogen; -alkyl; -alkenyl;-aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y-aryl;alkyl-Y-alkenyl; and alkyl or alkenyl substituted by one or moresubstituents selected from the group consisting of: —OH; -halogen;—N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃; -aryl;-heteroaryl; -heterocyclyl; —CO-aryl; and —CO-heteroaryl; R₄ is alkyl oralkenyl, which may be interrupted by one or more —O— groups; each R₃ isindependently H or C₁₋₁₀ alkyl; each Y is independently —O— or—S(O)₀₋₂—; n is 0 to 4; and each R present is independently selectedfrom the group consisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogenand trifluoromethyl; or a pharmaceutically acceptable salt thereof. 22.A compound or salt of claim 21 wherein R₁ is —(CH₂)₀₋₃-substitutedphenyl.
 23. A compound or salt of claim 21 wherein R₂ is H or alkyl. 24.A compound or salt of claim 21 wherein R₂ is -alkyl-O-alkyl.
 25. Acompound of the Formula (IV):

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; R₁₀ is selectedfrom the group consisting of: —H; -alkyl; -alkylaryl; -alkenyl; and-aryl; R₂ is selected from the group consisting of: -hydrogen; -alkyl;-alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl;-alkyl-Y-aryl; -alkyl-Y-alkenyl; and alkyl or alkenyl substituted by oneor more substituents selected from the group consisting of: —OH;-halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃;-aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and —CO-heteroaryl; each R₃is independently H or C₁₋₁₀ alkyl; each Y is independently —O— or—S(O)₀₋₂—; n is 0 to 4; and each R present is independently selectedfrom the group consisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogenand trifluoromethyl; or a pharmaceutically acceptable salt thereof. 26.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound or salt of claim 1 and a pharmaceuticallyacceptable carrier.
 27. A pharmaceutical composition comprising atherapeutically effective amount of a compound or salt of claim 11 and apharmaceutically acceptable carrier.
 28. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound or salt ofclaim 21 and a pharmaceutically acceptable carrier.
 29. A method ofinducing cytokine biosynthesis in an animal comprising administering atherapeutically effective amount of a compound or salt of claim 1 to theanimal.
 30. The method of claim 29 wherein the cytokine is IFN-α.
 31. Amethod of inducing cytokine biosynthesis in an animal comprisingadministering a therapeutically effective amount of a compound or saltof claim 11 to the animal.
 32. The method of claim 31 wherein thecytokine is IFN-α.
 33. A method of treating a viral disease in an animalcomprising administering a therapeutically effective amount of acompound or salt of claim 1 to the animal.
 34. A method of treating aneoplastic disease in an animal comprising administering atherapeutically effective amount of a compound or salt of claim 1 to theanimal.
 35. A method of treating a viral disease in an animal comprisingadministering a therapeutically effective amount of a compound or saltof claim 11 to the animal.
 36. A method of treating a neoplastic diseasein an animal comprising administering a therapeutically effective amountof a compound or salt of claim 11 to the animal.
 37. A method ofinducing cytokine biosynthesis in an animal comprising administering atheraputically effective amount of a compound or salt of claim 21 to theanimal.
 38. The method of claim 37 wherein the cytokine is IFN-α.
 39. Amethod of treating a viral disease in an animal comprising administeringa therapeutically effective amount of a compound or salt of claim 21 tothe animal.
 40. A method of treating a neoplastic disease in an animalcomprising administering a therapeutically effective amount of acompound or salt of claim 21 to the animal.
 41. A compound of theFormula (V):

wherein X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; R₁ is selectedfrom the group consisting of: -aryl; -alkenyl; —R₄-aryl; and—(CH₂)₁₋₁₀—C≡C—R₁₀; R₂ is selected from the group consisting of:-hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl;-alkyl-Y-alkyl; -alkyl-Y-alkenyl; -alkyl-Y-aryl; and alkyl or alkenylsubstituted by one or more substituents selected from the groupconsisting of: —OH; -halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl;—CO—O—C₁₋₁₀ alkyl; —N₃; -aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and—CO-heteroaryl; R₄ is alkyl or alkenyl, which may be interrupted by oneor more —O— groups; each R₃ is independently H or C₁₋₁₀ alkyl; R₁₀ isselected from the group consisting of H, alkyl, alkenyl, aryl, and-alkylaryl; each Y is independently —O— or —S(O)₀₋₂—; n is 0 to 4; andeach R present is independently selected from the group consisting ofC₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 42. A compound of the Formula(VI):

wherein X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; R₁ is selectedfrom the group consisting of: -aryl; -alkenyl; —R₄-aryl; and-(CH₂)₁₋₁₀—C≡C—R₁₀; R₂ is selected from the group consisting of:-hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl;-alkyl-Y-alkyl; -alkyl-Y-alkenyl; -alkyl-Y-aryl; and alkyl or alkenylsubstituted by one or more substituents selected from the groupconsisting of: —OH; -halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl;—CO—O—C₁₋₁₀ alkyl; —N₃; -aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and—CO-heteroaryl; R₄ is alkyl or alkenyl, which may be interrupted by oneor more —O— groups; each R₃ is independently H or C₁₋₁₀ alkyl; R₁₀ isselected from the group consisting of H, alkyl, alkenyl, aryl,-alkylaryl; each Y is independently —O— or —S(O)₀₋₂—; n is 0 to 4; andeach R present is independently selected from the group consisting ofC₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 43. A compound of the Formula(VII):

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; R₁ is selectedfrom the group consisting of: -aryl; -alkenyl; —R₄-aryl; and—(CH₂)₁₋₁₀—C≡C—R₁₀; R₄ is alkyl or alkenyl, which may be interrupted byone or more —O— groups; each R₃ is independently H or C₁₋₁₀ alkyl; R₁₀is selected from the group consisting of H, alkyl, alkenyl, aryl, and-alkylaryl; n is 0 to 4; and each R present is independently selectedfrom the group consisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogenand trifluoromethyl; or a pharmaceutically acceptable salt thereof. 44.A compound of the Formula (VIII):

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; R₁ is selectedfrom the group consisting of: -aryl; -alkenyl; —R₄-aryl; and—(CH₂)₁₋₁₀—C≡C—R₁₀; R₂ is selected from the group consisting of:-hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl:-alkyl-Y-alkyl; -alkyl-Y-alkenyl; -alkyl-Y-aryl; and -alkyl or alkenylsubstituted by one or more substituents selected from the groupconsisting of: —OH; -halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl;—CO—O—C₁₋₁₀ alkyl; —N₃; -aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and—CO-heteroaryl; R₄ is alkyl or alkenyl, which may be interrupted by oneor more —O— groups; each R₃ is independently H or C₁₋₁₀ alkyl; R₁₀ isselected from the group consisting of H, alkyl, alkenyl, aryl, and-alkylaryl; each Y is independently —O— or —S(O)₀₋₂—; n is 0 to 4; eachR present is independently selected from the group consisting of C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, hydroxy, halogen and trifluoromethyl; and R₇ istert-butyl or benzyl; or a pharmaceutically acceptable salt thereof. 45.A compound of the Formula (IX)

wherein: X is —CHR₃—, —CHR₃-alkyl-, or —CHR₃-alkenyl-; R₁ is selectedfrom the group consisting of: -aryl; -alkenyl; —R₄-aryl; and—(CH₂)₁₋₁₀—C≡CH; R₂ is selected from the group consisting of: -hydrogen;-alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl;-alkyl-Y-alkenyl; -alkyl-Y-aryl; and alkyl or alkenyl substituted by oneor more substituents selected from the group consisting of: —OH;-halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃;-aryl; -heteroaryl; -heterocyclyl; —CO-aryl; and —CO-heteroaryl; R₄ isalkyl or alkenyl, which may be interrupted by one or more —O— groups;each R₃ is independently H or C₁₋₁₀ alkyl; each Y is independently —O—or —S(O)₀₋₂—; n is 0 to 4; and each R present is independently selectedfrom the group consisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, hydroxy, halogenand trifluoromethyl; or a pharmaceutically acceptable salt thereof.